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Current Research and Scholarly Interests

My research interests cover a number of areas in Pediatric Endocrinology and Diabetes. I am PI of the Stanford Center for the NIH-funded Type-1 Diabetes TrialNet group. TrialNet conducts clinical trials directed at preventing or delaying the onset of Type 1 diabetes. I am an investigator in DirecNet, another NIH-funded study group, which is devoted to evaluating glucose sensors and the role of technology on the management of diabetes.

Clinical Trials

Accelerometer Use in the Prevention of Exercise-Associated Hypoglycemia in Type 1 Diabetes: Outpatient Exercise ProtocolRecruiting

Manually suspending an insulin pump at the beginning of aerobic exercise reduces the risk of
exercise-associated hypoglycemia (low blood sugar) in patients with type 1 diabetes (T1D).
However, since patients with T1D often do not make exercise-related adjustments to their
insulin regimen, our group has developed an algorithm to initiate pump suspension in a
user-independent manner upon projecting exercise-associated hypoglycemia. The current study
seeks to test the efficacy of this algorithm by asking users to participate in a sports camp
while wearing an insulin pump, continuous glucose monitor, and accelerometer/heart rate
monitor (to detect exercise), which will communicate electronically to a pump shutoff
algorithm. On one of the days the algorithm will be used, while on the other day their normal
insulin rate will continue for comparative purposes.
The investigators hypothesize that the use of an accelerometer-augmented computer algorithm
for insulin pump suspension during exercise will result in significantly fewer episodes of
hypoglycemia (both during exercise and in post-exercise monitoring) than in exercise without
a pump suspension algorithm.

This is a three-arm, 1:1:1 randomized, placebo controlled, double- blinded trial in which at
least 28 subjects will receive active Anti-Thymocyte Globulin and Granulocyte
colony-stimulating factor (ATG-GCSF), at least 28 subjects will receive ATG alone and at
least 28 subjects will receive placebo alone within 100 days from diagnosis of Type 1
Diabetes (T1D).
The primary objective of the study will be to determine the safety and ability of low dose
ATG plus GCSF and low dose ATG alone to retain/enhance C-peptide production in new onset T1D
patients demonstrating residual beta cell function.

CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1Recruiting

The study is a 2-arm, multicenter, 1:1 randomized, placebo controlled clinical trial.
All subjects will receive close monitoring for development of AGT or T1DM. Subjects will
receive Abatacept or placebo and close monitoring for development of AGT or T1DM. To assess
the safety, efficacy, and mode of action of Abatacept to prevent AGT and T1DM.
The primary objective is to determine whether intervention with Abatacept will prevent or
delay the development of AGT in at-risk autoantibody positive non-diabetic relatives of
patients with T1DM.
Secondary outcomes include: the effect of Abatacept on the incidence of T1DM; analyses of
C-peptide and other measures from the OGTT; safety and tolerability; and mechanistic
outcomes.

The study is a 2 arm, multi-center, randomized, open-labeled clinical trial designed to
assess the effects of varying doses and schedules of oral insulin on immunological and
metabolic markers in relatives at risk for type 1 diabetes (T1D).

Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes MellitusRecruiting

Type 1 diabetes (T1D) is an autoimmune disease. This means that the immune system (the part
of the body which helps fight infections) mistakenly attacks and destroys the cells that
produce insulin (islet cells found in the pancreas). As these cells are destroyed, the body's
ability to produce insulin decreases. There is evidence suggesting that repeated oral
administration of an autoantigen (the same protein that the immune system is reacting to) may
introduce a protective immunity and cause the immune system to stop its attack. An earlier,
large scale study was done to see if oral insulin could delay or prevent the development of
Type 1 diabetes in relatives at risk for developing Type 1 diabetes. The overall results
showed that for the entire study population, oral insulin did not delay or prevent Type 1
diabetes. However, an analysis that was done after the conclusion of the trial suggested a
potential beneficial effect in a subgroup of participants. The participants who seemed to
benefit from oral insulin had higher levels of insulin autoantibodies which are directed
against insulin itself ( called mIAA).
The Type 1 Diabetes TrialNet study group will further explore the potential role of oral
insulin to delay or prevent Type 1 diabetes in a similar group of people. The study will also
include a secondary group of individuals at different levels of risk than those in the
primary cohort to gather information for future studies.

RATIONALE
The accrual of data from the laboratory and from epidemiologic and prevention trials has
improved the understanding of the etiology and pathogenesis of type 1 diabetes mellitus
(T1DM). Genetic and immunologic factors play a key role in the development of T1DM, and
characterization of the early metabolic abnormalities in T1DM is steadily increasing.
However, information regarding the natural history of T1DM remains incomplete. The TrialNet
Natural History Study of the Development of T1DM (Pathway to Prevention Study) has been
designed to clarify this picture, and in so doing, will contribute to the development and
implementation of studies aimed at prevention of and early treatment in T1DM.
Purpose:
TrialNet is an international network dedicated to the study, prevention, and early treatment
of type 1 diabetes. TrialNet sites are located throughout the United States, Canada, Finland,
United Kingdom, Italy, Germany, Sweden, Australia, and New Zealand. TrialNet is dedicated to
testing new approaches to the prevention of and early intervention for type 1 diabetes.
The goal of the TrialNet Natural History Study of the Development of Type 1 Diabetes is to
enhance our understanding of the demographic, immunologic, and metabolic characteristics of
individuals at risk for developing type 1 diabetes.
The Natural History Study will screen relatives of people with type 1 diabetes to identify
those at risk for developing the disease. Relatives of people with type 1 diabetes have about
a 5% percent chance of being positive for the antibodies associated with diabetes. TrialNet
will identify adults and children at risk for developing diabetes by testing for the presence
of these antibodies in the blood. A positive antibody test is an early indication that damage
to insulin-secreting cells may have begun. If this test is positive, additional testing will
be offered to determine the likelihood that a person may develop diabetes. Individuals with
antibodies will be offered the opportunity for further testing to determine their risk of
developing diabetes over the next 5 years and to receive close monitoring for the development
of diabetes.

Teplizumab for Prevention of Type 1 Diabetes In Relatives "At-Risk"Recruiting

The study will determine whether the anti-CD3 monoclonal antibody, teplizumab, can help to
prevent or delay the onset of type 1 diabetes (T1D) in relatives determined to be at very
high risk for developing the disease. Teplizumab has been studied in new onset type 1
diabetes for testing of efficacy and safety in previous studies; other studies are currently
in progress. The results of previous studies indicate that teplizumab reduces the loss of
insulin production during the first year after diagnosis in individuals with type 1 diabetes.
The purpose of this study is to determine if teplizumab can interdict the immune process that
causes the destruction of insulin secreting beta cells in the pancreas during the
"pre-diabetic" state and thereby prevent or delay the onset of type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Based on previous research, study
doctors think that giving medicines to affect the immune system soon after diabetes is
diagnosed may stop, delay or decrease the destruction of beta cells, resulting in better
glucose control.
Researchers believe that tocilizumab could have some effect on the cells in the immune system
that are thought to be involved in the development of type 1 diabetes. This study will test
whether tocilizumab can help preserve or delay destruction of remaining beta cells in people
recently diagnosed type 1 diabetes.

Comparison of Transdermal and Oral Estrogens in Adolescent Girls With Ovarian FailureNot Recruiting

To directly compare the safety (by laboratory evaluation) and efficacy (feminization and
growth) of three commonly used estrogen preparations in adolescent patients with ovarian
failure, either due to congenital causes (Turner syndrome) or medical therapies. We
hypothesize that transdermal estrogen will have equivalent efficacy and a more favorable
safety profile in comparison with conventional oral estrogen replacement.

Stanford is currently not accepting patients for this trial.For more information, please contact Sejal Shah, (650) 723 - 5791.

The purpose of this study is to evaluate a treat-to-range automated insulin management system
using continuous glucose monitoring (CGM) and subcutaneous insulin pump infusion in
individuals with type 1 diabetes.

Stanford is currently not accepting patients for this trial.For more information, please contact Kari Benassi, RN, FNP, 650-736-8948.

Pilot Study to Evaluate a Method of Controlling High Blood Sugar in the Pediatric Intensive Care UnitNot Recruiting

Recent studies of adult intensive care unit (ICU) patients have shown significantly decreased
morbidity and mortality when blood sugar concentrations are closely controlled. The safety
and efficacy of this type of blood sugar management has not been studied in the pediatric ICU
population. Based on the current pediatric literature data as well as our extensive
retrospective study, blood sugar concentrations have a potentially profound role to play
among PICU patients. In preparation for a multi-center randomized control trial, we propose a
prospective feasibility study to evaluate the safety and effectiveness of using an insulin
delivery algorithm to manage blood sugar in the PICU. Our hypothesis for this feasibility
trial is that uniformly monitoring and controlling blood glucose with a
Discrete-Closed-Loop(DCL) insulin delivery algorithm will be an effective, safe, and
consistent means of delivering insulin to manage glucose in the pediatric intensive care
unit.

Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks the
insulin-producing beta cells in the pancreas. Without these beta cells, the body cannot
maintain proper blood glucose levels in response to daily activities such as eating or
exercise. With fewer insulin producing cells blood glucose increases, causing hunger, thirst,
and unexplained weight loss. By the time these symptoms develop, 80-90% of a person's beta
cells have already been destroyed. However, this also means that between 10-20% of these
cells remain that continue to produce insulin.
Scientists have learned that two types of immune cells, B cells and T cells, are involved in
causing type 1 diabetes. T cells are responsible for attacking and destroying the beta cells
that make insulin. Although they don't attack insulin producing cells, B cells may be what
trigger the T cells to attack.
This study will investigate the use of rituximab to see if it can help lower the number of
immune B cells thereby preventing the destruction of any remaining insulin producing beta
cells that remain at diagnosis. Rituximab is approved by the Food and Drug Administration
(FDA) for the treatment of a condition called B-lymphocyte lymphoma. Its effects on the
immune system are well understood through its use in organ transplantation. Research has
shown that rituximab might be helpful in treating other conditions caused by T cells and B
cells, including type 1 diabetes. The goal of this study is to find out if rituximab can
preserve residual insulin secretion and prevent further beta cell destruction in type 1
diabetes.

Stanford is currently not accepting patients for this trial.For more information, please contact Allison Rigby, (877) 232 - 5182.

Type 1 diabetes is a condition that is caused in part by an abnormality of the immune system
which occurs when T cells, which are part of the immune system, damage the insulin secreting
cells (islet cells) in the pancreas. Although it is known that T cells are important
mediators of the disease, progress in the development of reliable T cell assays has been
modest. The purpose of this study is to learn which T cell assays are most reliable and
reproducible so that the investigators can improve their understanding about how type 1
diabetes occurs.

Stanford is currently not accepting patients for this trial.For more information, please contact Alison Rigby, (877) 232 - 5182.

Abstract

The objective of this study was to determine the safety, feasibility, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system compared with predictive low-glucose insulin suspension (PLGS) alone in overnight glucose control.A 42-night trial was conducted in 30 individuals with type 1 diabetes in the age range 15-45 years. Participants were randomly assigned each night to either PHHM or PLGS and were blinded to the assignment. The system suspended the insulin pump on both the PHHM and PLGS nights for predicted hypoglycemia but delivered correction boluses for predicted hyperglycemia on PHHM nights only. The primary outcome was the percentage of time spent in a sensor glucose range of 70-180 mg/dL during the overnight period.The addition of automated insulin delivery with PHHM increased the time spent in the target range (70-180 mg/dL) from 71 ± 10% during PLGS nights to 78 ± 10% during PHHM nights (P < 0.001). The average morning blood glucose concentration improved from 163 ± 23 mg/dL after PLGS nights to 142 ± 18 mg/dL after PHHM nights (P < 0.001). Various sensor-measured hypoglycemic outcomes were similar on PLGS and PHHM nights. All participants completed 42 nights with no episodes of severe hypoglycemia, diabetic ketoacidosis, or other study- or device-related adverse events.The addition of a predictive hyperglycemia minimization component to our existing PLGS system was shown to be safe, feasible, and effective in overnight glucose control.

Abstract

The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity.We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220.We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study.Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas.National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Abstract

Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

Abstract

To determine the safety and efficacy of an automated unified safety system (USS) in providing overnight closed-loop (OCL) control in children and adolescents with type 1 diabetes attending diabetes summer camps.RESEARCH DESIGN AND METHODS: The Diabetes Assistant (DIAS) USS used the Dexcom G4P glucose sensor (Dexcom) and t:slim insulin pump (Tandem Diabetes Care). An initial inpatient study was completed for 12 participants to evaluate safety. For the main camp study, 20 participants with type 1 diabetes were randomized to either OCL or sensor-augmented therapy (control conditions) per night over the course of a 5- to 6-day diabetes camp.RESULTS: Subjects completed 54 OCL nights and 52 control nights. On an intention-to-treat basis, with glucose data analyzed regardless of system status, the median percent time in range, from 70-150 mg/dL, was 62% (29, 87) for OCL nights versus 55% (25, 80) for sensor-augmented pump therapy (P = 0.233). A per-protocol analysis allowed for assessment of algorithm performance. The median percent time in range, from 70-150 mg/dL, was 73% (50, 89) for OCL nights (n = 41) versus 52% (24, 83) for control conditions (n = 39) (P = 0.037). There was less time spent in the hypoglycemic range <50, <60, and <70 mg/dL during OCL compared with the control period (P = 0.019, P = 0.009, and P = 0.023, respectively).CONCLUSIONS: The DIAS USS algorithm is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.

Abstract

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

Abstract

Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes.Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399.145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups.Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge.US National Institutes of Health.

Abstract

To determine the individual persistence of the relationship between mean sensor glucose (MG) concentrations and hemoglobin A(1c) (A1C) from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (CGM) Randomized Trial.MG was calculated using CGM data for 3 months before A1C measurements at 3, 6, 9, and 12 months for the CGM group and at 9 and 12 months for the control group. An MG-to-A1C ratio was included in analysis for subjects who averaged ≥4 days/week of CGM use.Spearman correlations of the MG-to-A1C ratio between consecutive visits 3 months apart ranged from 0.70 to 0.79. The correlations for children and youth were slightly smaller than those for adults. No meaningful differences were observed by device type or change in A1C.Individual variations in the rate of hemoglobin glycation are persistent and contribute to the inaccuracy in estimating MGs calculated from A1C levels.

Abstract

To determine the relationship between mean sensor glucose concentrations and hemoglobin A(1c) (HbA(1c)) values measured in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications laboratory at the University of Minnesota in a cohort of subjects with type 1 diabetes from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial.Near-continuous glucose sensor data (≥ 4 days/week) were collected for 3 months before a central laboratory-measured HbA(1c) was performed for 252 subjects aged 8-74 years, the majority of whom had stable HbA(1c) values (77% within ± 0.4% of the patient mean).The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA(1c) was 24.4 mg/dL (22.0-26.7) for each 1% change in HbA(1c), with an intercept of -16.2 mg/dL (-32.9 to 0.6). Although the slope did not vary with age or sex, there was substantial individual variability, with mean sensor glucose concentrations ranging from 128 to 187 mg/dL for an HbA(1c) of 6.9-7.1%. The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL.There is substantial individual variability between the measured versus calculated mean glucose concentrations. Consequently, estimated average glucose concentrations calculated from measured HbA(1c) values should be used with caution.

Abstract

This study determined the feasibility and efficacy of an automated proportional-integral-derivative with insulin feedback (PID-IFB) controller in overnight closed-loop (OCL) control of children and adolescents with type 1 diabetes over multiple days in a diabetes camp setting.The Medtronic (Northridge, CA) Android™ (Google, Mountain View, CA)-based PID-IFB system consists of the Medtronic Minimed Revel™ 2.0 pump and Enlite™ sensor, a control algorithm residing on an Android phone, a translator, and remote monitoring capabilities. An inpatient study was completed for 16 participants to determine feasibility. For the camp study, subjects with type 1 diabetes were randomized to either OCL or sensor-augmented pump therapy (control conditions) per night for up to 6 nights at diabetes camp.During the camp study, 21 subjects completed 50 OCL nights and 52 control nights. Based on intention to treat, the median time spent in range, from 70 to 150 mg/dL, was greater during OCL at 66.4% (n = 55) versus 50.6% (n = 52) during the control period (P = 0.004). A per-protocol analysis allowed for assessment of algorithm performance with the median percentage time in range, 70-150 mg/dL, being 75.5% (n = 37) for OCL versus 47.6% (n = 32) for the control period (P

Abstract

To identify patterns of outpatient care associated with diabetic ketoacidosis (DKA) among pediatric patients with type 1 diabetes (T1D).Retrospective cohort study using Medicaid claims data from 2009 to 2012 for children with T1D enrolled ≥365 consecutive days in California Children's Services, a Title V program for low-income children with chronic disease. Outcome was DKA hospitalization >30 days after enrollment. Outpatient visits to primary care, endocrinology, pharmacies, and emergency departments (EDs) were assessed during the 6 months before an index date: either date of first DKA hospitalization or end of enrollment for those without DKA. Univariate and multivariate analysis was used to evaluate independent associations between DKA and outpatient care at clinically meaningful intervals preceding the index date.Among 5263 children with T1D, 16.7% experienced DKA during the study period. Patients with DKA were more likely to have had an ED visit (adjusted odds ratio [aOR] 3.99, 95% confidence interval [CI]: 2.60-6.13) or a nonpreventive primary care visit (aOR 1.35, 95% CI: 1.01-1.79) within 14 days before the index date, and less likely to have visited an endocrinologist (aOR 0.76, 95% CI: 0.65-0.89) within the preceding 120 days. Preventive visits and pharmacy claims were not associated with DKA.For children with T1D, recent ED visits and long intervals without subspecialty care are important signals of impending DKA. Combined with other known risk factors, these health-use indicators could be used to inform clinical and case management interventions that aim to prevent DKA hospitalizations.

Abstract

To compare fasting insulin-like growth factor binding protein 1 (IGFBP-1) to other fasting indices as a surrogate marker of insulin sensitivity and resistance calculated from a 3-hour oral glucose tolerance test (oGTT).Fasting IGFBP-1 and oGTT were performed at 0 (n = 77), 52 (n = 54), and 100 (n = 38) weeks in a study investigating metformin treatment of obesity in adolescents. Insulin area-under-the-curve (IAUC) and the composite insulin sensitivity index (CISI) calculated from the oGTT were compared to fasting IGFBP-1, homeostasis model assessment-insulin resistance, and corrected insulin release at the glucose peak (CIRgp).IGFBP-1 and the ratio of IGFBP-1 to fasting insulin were significantly correlated with indices based on timed sampling, including IAUC, CISI, and CIRgp. In addition, a significant effect of IGFBP-1, but not IGFBP-1 to insulin at time zero, was observed for IAUC and CISI.Our results indicate that fasting IGFBP-1 may be a useful marker of insulin sensitivity and secretion.

Abstract

Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor-based overnight predictive low-glucose suspend (PLGS) system.In two age-groups of children with type 1 diabetes (11-14 and 4-10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight.Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11-14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4-10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P < 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P < 0.001) in the 11-14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4-10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis.In 4-14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

Abstract

Hypoglycemia remains an impediment to good glycemic control, with nocturnal hypoglycemia being particularly dangerous. Information on major contributors to nocturnal hypoglycemia remains critical for understanding and mitigating risk.Continuous glucose monitoring (CGM) data for 855 nights were studied, generated by 45 subjects 15-45 years of age with hemoglobin A1c (HbA1c) levels of ≤8.0% who participated in a larger randomized study. Factors assessed for potential association with nocturnal hypoglycemia (CGM measurement of <60 mg/dL for ≥30 min) included bedtime blood glucose (BG), exercise intensity, bedtime snack, insulin on board, day of the week, previous daytime hypoglycemia, age, gender, HbA1c level, diabetes duration, daily basal insulin, and daily insulin dose.Hypoglycemia occurred during 221 of 885 (25%) nights and was more frequent with younger age (P<0.001), lower HbA1c levels (P=0.006), medium/high-intensity exercise during the preceding day (P=0.003), and the occurrence of antecedent daytime hypoglycemia (P=0.001). There was a trend for lower bedtime BG levels to be associated with more frequent nocturnal hypoglycemia (P=0.10). Bedtime snack, before bedtime insulin bolus, weekend versus weekday, gender, and daily basal and bolus insulin were not associated with nocturnal hypoglycemia.Awareness that HbA1c level, exercise, bedtime BG level, and daytime hypoglycemia are all modifiable factors associated with nocturnal hypoglycemia may help patients and providers decrease the risk of hypoglycemia at night. Risk for nocturnal hypoglycemia increased in a linear fashion across the range of variables, with no clear-cut thresholds to guide clinicians or patients for any particular night.

Abstract

We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D.The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors.The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all).The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers.

Abstract

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

Abstract

Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data.The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured.Here, we measured β cell death with an assay that detects β cell-derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants.In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not.We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.Clinicaltrials.gov NCT00097292.Funding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association.

Abstract

We recently developed new electrochemiluminescence (ECL) insulin autoantibody (IAA) and glutamic acid decarboxylase 65 autoantibody (GADA) assays that discriminate high-affinity, high-risk diabetes-specific autoantibodies from low-affinity, low-risk islet autoantibodies (iAbs) detected by radioassay (RAD). Here, we report a further validation of the ECL-IAA and -GADA assays in 3,484 TrialNet study participants. The ECL assay and RAD were congruent in those with prediabetes and in subjects with multiple autoantibodies, but only 24% (P<0.0001) of single RAD-IAA-positive and 46% (P<0.0001) of single RAD-GADA-positive were confirmed by the ECL-IAA and -GADA assays, respectively. During a follow-up (mean, 2.4 years), 51% of RAD-IAA-positive and 63% of RAD-GADA-positive subjects not confirmed by ECL became iAb negative, compared with only 17% of RAD-IAA-positive (P<0.0001) and 15% of RAD-GADA-positive (P<0.0001) subjects confirmed by ECL assays. Among subjects with multiple iAbs, diabetes-free survival was significantly shorter if IAA or GADA was positive by ECL and negative by RAD than if IAA or GADA was negative by ECL and positive by RAD (P<0.019 and P<0.0001, respectively). Both positive and negative predictive values in terms of progression to type 1 diabetes mellitus were superior for ECL-IAA and ECL-GADA, compared with RADs. The prevalence of the high-risk human leukocyte antigen-DR3/4, DQB1*0302 genotype was significantly higher in subjects with RAD-IAA or RAD-GADA confirmed by ECL. In conclusion, both ECL-IAA and -GADA are more disease-specific and better able to predict the risk of progression to type 1 diabetes mellitus than the current standard RADs.

Abstract

Closed-loop control of blood glucose levels in people with type 1 diabetes offers the potential to reduce the incidence of diabetes complications and reduce the patients' burden, particularly if meals do not need to be announced. We therefore tested a closed-loop algorithm that does not require meal announcement.A multiple model probabilistic predictive controller (MMPPC) was assessed on four patients, revised to improve performance, and then assessed on six additional patients. Each inpatient admission lasted for 32 h with five unannounced meals containing approximately 1 g/kg of carbohydrate per admission. The system used an Abbott Diabetes Care (Alameda, CA) Navigator(®) continuous glucose monitor (CGM) and Insulet (Bedford, MA) Omnipod(®) insulin pump, with the MMPPC implemented through the artificial pancreas system platform. The controller was initialized only with the patient's total daily dose and daily basal pattern.On a 24-h basis, the first cohort had mean reference and CGM readings of 179 and 167 mg/dL, respectively, with 53% and 62%, respectively, of readings between 70 and 180 mg/dL and four treatments for glucose values <70 mg/dL. The second cohort had mean reference and CGM readings of 161 and 142 mg/dL, respectively, with 63% and 78%, respectively, of the time spent euglycemic. There was one controller-induced hypoglycemic episode. For the 30 unannounced meals in the second cohort, the mean reference and CGM premeal, postmeal maximum, and 3-h postmeal values were 139 and 132, 223 and 208, and 168 and 156 mg/dL, respectively.The MMPPC, tested in-clinic against repeated, large, unannounced meals, maintained reasonable glycemic control with a mean blood glucose level that would equate to a mean glycated hemoglobin value of 7.2%, with only one controller-induced hypoglycemic event occurring in the second cohort.

Abstract

This pilot study evaluated the difference in accuracy between the Bayer Contour® Next (CN) and HemoCue® (HC) glucose monitoring systems in children with type 1 diabetes participating in overnight closed-loop studies. Subjects aged 10-18 years old were admitted to a clinical research center and glucose values were obtained every 30 minutes overnight. Glucose values were measured using whole blood samples for CN and HC readings and results were compared to Yellow Springs Instrument (YSI) reference values obtained with plasma from the same sample. System accuracy was compared using mean absolute relative difference (MARD) and International Organization for Standardization (ISO) accuracy standards. A total of 28 subjects were enrolled in the study. Glucose measurements were evaluated at 457 time points. CN performed better than HC with an average MARD of 3.13% compared to 10.73% for HC (P < .001). With a limited sample size, CN met ISO criteria (2003 and 2013) at all glucose ranges while HC did not. CN performed very well, and would make an excellent meter for future closed-loop studies outside of a research center.

Abstract

We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.Eighty-seven subjects (aged 8-40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome-baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year-showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (P = 0.03). Odds ratio for loss of C-peptide to <0.2 nmol/L following rituximab was 0.565 (P = 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.

Abstract

This study tested the feasibility and effectiveness of remote continuous glucose monitoring (CGM) in a diabetes camp setting.Twenty campers (7-21 years old) with type 1 diabetes were enrolled at each of three camp sessions lasting 5-6 days. On alternating nights, 10 campers were randomized to usual wear of a Dexcom (San Diego, CA) G4™ PLATINUM CGM system, and 10 were randomized to remote monitoring with the Dexcom G4 PLATINUM communicating with the Diabetes Assistant, a cell phone platform, to allow wireless transmission of CGM values. Up to 15 individual graphs and sensor values could be displayed on a single remote monitor or portable tablet. An alarm was triggered for values <70 mg/dL, and treatment was given for meter-confirmed hypoglycemia. The primary end point was to decrease the duration of hypoglycemic episodes <50 mg/dL.There were 320 nights of CGM data and 197 hypoglycemic events. Of the remote monitoring alarms, 79% were true (meter reading of <70 mg/dL). With remote monitoring, 100% of alarms were responded to, whereas without remote monitoring only 54% of alarms were responded to. The median duration of hypoglycemic events <70 mg/dL was 35 min without remote monitoring and 30 min with remote monitoring (P=0.078). Remote monitoring significantly decreased prolonged hypoglycemic events, eliminating all events <50 mg/dL lasting longer than 30 min as well as all events <70 mg/dL lasting more than 2 h.Remote monitoring is feasible at diabetes camps and effective in reducing the risk of prolonged nocturnal hypoglycemia. This technology will facilitate forthcoming studies to evaluate the efficacy of automated closed-loop systems in the camp setting.

Abstract

This study compared infusion set function for up to 1 week using either a Teflon(®) (Dupont(™), Wilmington, DE) catheter or a steel catheter for insulin pump therapy in type 1 diabetes mellitus.Twenty subjects participating in a randomized, open-labeled, crossover study were asked to wear two Quick-Set(®) and two Sure-T(®) infusion sets (both from Medtronic Minimed, Northridge, CA) until the infusion set failed or was worn for 1 week. All subjects wore a MiniMed continuous glucose monitoring system for the duration of the study.One subject withdrew from the study. There were 38 weeks of Sure-T wear and 39 weeks of Quick-Set wear with no difference in the survival curves of the infusion sets. There was, however, a 15% initial failure rate with the Teflon infusion set. After 7 days, both types of infusion sets had a 64% failure rate. Overall, 30% failed because of hyperglycemia and a failed correction dose, 13% were removed for pain, 10% were pulled out by accident, 10% had erythema and/or induration of>10 mm, 5% fell out because of loss of adhesion, and 4% were removed for infection. The main predictor of length of wear was the individual subject. There was no increase in hyperglycemia or daily insulin requirements when an infusion set was successfully used for 7 days (n=25 of 77 weeks).We found no difference between steel and Teflon infusion sets in their function over 7 days, although 15% of Teflon sets failed because of kinking on insertion. The strongest predictor of prolonged 7-day infusion set function was the individual subject, not the type of infusion set.

Abstract

To test the effects of a three-year, community-based, multi-component, multi-level, multi-setting (MMM) approach for treating overweight and obese children.Two-arm, parallel group, randomized controlled trial with measures at baseline, 12, 24, and 36months after randomization.Seven through eleven year old, overweight and obese children (BMI≥85th percentile) and their parents/caregivers recruited from community locations in low-income, primarily Latino neighborhoods in Northern California.Families are randomized to the MMM intervention versus a community health education active-placebo comparison intervention. Interventions last for three years for each participant. The MMM intervention includes a community-based after school team sports program designed specifically for overweight and obese children, a home-based family intervention to reduce screen time, alter the home food/eating environment, and promote self-regulatory skills for eating and activity behavior change, and a primary care behavioral counseling intervention linked to the community and home interventions. The active-placebo comparison intervention includes semi-annual health education home visits, monthly health education newsletters for children and for parents/guardians, and a series of community-based health education events for families.Body mass index trajectory over the three-year study. Secondary outcome measures include waist circumference, triceps skinfold thickness, accelerometer-measured physical activity, 24-hour dietary recalls, screen time and other sedentary behaviors, blood pressure, fasting lipids, glucose, insulin, hemoglobin A1c, C-reactive protein, alanine aminotransferase, and psychosocial measures.The Stanford GOALS trial is testing the efficacy of a novel community-based multi-component, multi-level, multi-setting treatment for childhood overweight and obesity in low-income, Latino families.

Abstract

Abstract Objective: Nocturnal hypoglycemia is a common problem with type 1 diabetes. In the home setting, we conducted a pilot study to evaluate the safety of a system consisting of an insulin pump and continuous glucose monitor communicating wirelessly with a bedside computer running an algorithm that temporarily suspends insulin delivery when hypoglycemia is predicted. Research Design and Methods: After the run-in phase, a 21-night randomized trial was conducted in which each night was randomly assigned 2:1 to have either the predictive low-glucose suspend (PLGS) system active (intervention night) or inactive (control night). Three predictive algorithm versions were studied sequentially during the study for a total of 252 intervention and 123 control nights. The trial included 19 participants 18-56 years old with type 1 diabetes (hemoglobin A1c level of 6.0-7.7%) who were current users of the MiniMed Paradigm(®) REAL-Time Revel™ System and Sof-sensor(®) glucose sensor (Medtronic Diabetes, Northridge, CA). Results: With the final algorithm, pump suspension occurred on 53% of 77 intervention nights. Mean morning glucose level was 144±48 mg/dL on the 77 intervention nights versus 133±57 mg/dL on the 37 control nights, with morning blood ketones >0.6 mmol/L following one intervention night. Overnight hypoglycemia was lower on intervention than control nights, with at least one value ≤70 mg/dL occurring on 16% versus 30% of nights, respectively, with the final algorithm. Conclusions: This study demonstrated that the PLGS system in the home setting is safe and feasible. The preliminary efficacy data appear promising with the final algorithm reducing nocturnal hypoglycemia by almost 50%.

Abstract

Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes.We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34.Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group.Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders.National Institutes of Health and Juvenile Diabetes Research Foundation.

Abstract

An insulin pump shutoff system can prevent nocturnal hypoglycemia and is a first step on the pathway toward a closed-loop artificial pancreas. In previous pump shutoff studies using a voting algorithm and a 1 min continuous glucose monitor (CGM), 80% of induced hypoglycemic events were prevented.The pump shutoff algorithm used in previous studies was revised to a single Kalman filter to reduce complexity, incorporate CGMs with different sample times, handle sensor signal dropouts, and enforce safety constraints on the allowable pump shutoff time.Retrospective testing of the new algorithm on previous clinical data sets indicated that, for the four cases where the previous algorithm failed (minimum reference glucose less than 60 mg/dl), the mean suspension start time was 30 min earlier than the previous algorithm. Inpatient studies of the new algorithm have been conducted on 16 subjects. The algorithm prevented hypoglycemia in 73% of subjects. Suspension-induced hyperglycemia is not assessed, because this study forced excessive basal insulin infusion rates.The new algorithm functioned well and is flexible enough to handle variable sensor sample times and sensor dropouts. It also provides a framework for handling sensor signal attenuations, which can be challenging, particularly when they occur overnight.

Abstract

To examine the feasibility of continuous glucose monitoring (CGM) use in very young children with type 1 diabetes (T1D).Twenty-three children less than 4 yr of age with T1D were provided with a FreeStyle Navigator(®) (n = 21) or a Paradigm(®) (n = 2) CGM device. At baseline, mean age was 3.0 ± 0.8 yr, mean hemoglobin A1c (HbA1c) was 8.0 ± 0.8%, 10 were using an insulin pump and 13 were on multiple daily injections. CGM use was evaluated over a 6-month period.Three children dropped out of the study before the end of 6 months. Among the 20 children who completed 6 months of follow-up, CGM use in month 6 was ≥6 d/wk in 9 (45%), 4 ≤ 6 d/wk in 2 (10%), and <4 d/wk in 9 (45%). Skin reactions were minimal. Although there was no detectable change in mean HbA1c between baseline and 6 months (7.9 and 8.0%, respectively), there was a high degree of parental satisfaction with CGM as measured on the CGM satisfaction scale questionnaire. A high percentage of glucose values were in the hyperglycemic range, and biochemical hypoglycemia was infrequent.More than 40% of very young children were able to safely use CGM on a near-daily basis after 6 months. CGM demonstrated frequent hyperglycemic excursions, with a large variability in glucose readings. Although improvement in glycemic control was not detected in the group as a whole, parental satisfaction with CGM was high.

Abstract

To describe the interrelationships of glycemic control measures: hemoglobin A1c (HbA1c), glycated albumin, fructosamine, 1,5-anhydroglucitrol (1,5-AG), and continuous glucose monitoring (CGM) in children and adolescents with type 1 diabetes.In total, 26 subjects of age 4-17 had HbA1c measurement followed within 14 d by three laboratory measures of glycemia and the collection of CGM glucose data (N = 21).Glycated albumin and fructosamine levels had a higher correlation with each other than with HbA1c. The correlation of 1,5-AG with HbA1c was lower (absolute r value = 0.25). All four measures had a similar degree of correlation with CGM-measured mean glucose (absolute r value = 0.50-0.56) and with hyperglycemic area under the curve (AUC) at 180 mg/dL (0.50-0.60).Each of the four measures (i.e., HbA1c, glycated albumin, fructosamine, and 1,5-AG) had a similar correlation with mean glucose and hyperglycemic AUC-180. 1,5-AG did not correlate with hyperglycemic AUC-180 better than did HbA1c.

Abstract

To determine if frequent exposures to hypoglycemia and hyperglycemia during early childhood lead to neurocognitive deficits and changes in brain anatomy.In this feasibility, cross-sectional study, young children, aged 3 to 10 years, with type 1 diabetes and age- and sex-matched healthy control (HC) subjects completed neuropsychologic (NP) testing and magnetic resonance imaging (MRI) scans of the brain.NP testing and MRI scanning was successfully completed in 98% of the type 1 diabetic and 93% of the HC children. A significant negative relationship between HbA1c and Wechsler Intelligence Scale for Children (WISC) verbal comprehension was observed. WISC index scores were significantly reduced in type 1 diabetic subjects who had experienced seizures. White matter volume did not show the expected increase with age in children with type 1 diabetes compared with HC children (diagnosis by age interaction, P=0.005). A similar trend was detected for hippocampal volume. Children with type 1 diabetes who had experienced seizures showed significantly reduced gray matter and white matter volumes relative to children with type 1 diabetes who had not experienced seizures.It is feasible to perform MRI and NP testing in young children with type 1 diabetes. Further, early signs of neuroanatomic variation may be present in this population. Larger cross-sectional and longitudinal studies of neurocognitive function and neuroanatomy are needed to define the effect of type 1 diabetes on the developing brain.

Abstract

The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes.In this multicentre, double-blind, randomised controlled trial, patients aged 6-45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375.112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1-112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47-15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]).Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions.US National Institutes of Health.

Abstract

Control algorithms that regulate blood glucose (BG) levels in individuals with type 1 diabetes mellitus face several fundamental challenges. Two of these are the asymmetric risk of clinical complications associated with low and high glucose levels and the irreversibility of insulin action when using only insulin. Both of these nonlinearities force a controller to be more conservative when uncertainties are high. We developed a novel extended model predictive controller (EMPC) that explicitly addresses these two challenges.Our extensions to model predictive control (MPC) operate in three ways. First, they explicitly minimize the combined risk of hypoglycemia and hyperglycemia. Second, they integrate the effect of prediction uncertainties into the risk. Third, they understand that future control actions will vary if measurements fall above or below predictions. Using the University of Virginia/Padova Simulator, we compared our novel controller (EMPC) against optimized versions of a proportional-integral-derivative (PID) controller, a traditional MPC, and a basal/bolus (BB) controller, as well as against published results of an independent MPC (IMPC). The BB controller was optimized retrospectively to serve as a bound on the possible performance.We tuned each controller, where possible, to minimize a published blood glucose risk index (BGRI). The simulated controllers (PID/MPC/EMPC/BB) provided BGRI values of 2.99/3.05/2.51/1.27 as compared to the published IMPC BGRI value of 4.10. These correspond to 73/79/84/92% of BG values lying in the euglycemic range (70-180 mg/dl), respectively, with mean BG levels of 151/156/147/140 mg/dl.The EMPC strategy extends MPC to explicitly address the issues of asymmetric glycemic risk and irreversible insulin action using estimated prediction uncertainties and an explicit risk function. This controller reduces the avoidable BGRI by 56% (p < .05) relative to a published MPC algorithm studied on a similar population.

Abstract

AIMS AND HYPOTHESIS: The optimal duration and frequency of short-term continuous glucose monitoring (CGM) to reflect long-term glycemia have not been determined. The Juvenile Diabetes Research Foundation CGM randomized trials provided a large dataset of longitudinal CGM data for this type of analysis.The analysis included 185 subjects who had 334 3-month intervals of CGM data meeting specific criteria. For various glucose indices, correlations (r²) were computed for the entire 3-month interval versus selected sampling periods ranging from 3 to 15 days. Other computed agreement measures included median relative absolute difference, values within ± 10% and ± 20% of full value, and median absolute difference.As would be expected, the more days of glucose data that were sampled, the higher the correlation with the full 3 months of data. For 3 days of sampling, the r² value ranged from 0.32 to 0.47, evaluating mean glucose, percentage of values 71-180 mg/dL, percentage of values > 180 mg/dL, percentage of values ≤ 70 mg/dL, and coefficient of variation; in contrast, for 15 days of sampling, the r² values ranged from 0.66 to 0.75. The results were similar when the analysis intervals were stratified by age group (8-14, 15-24, and ≥ 25 years), by baseline hemoglobin A1c level (< 7.0% and ≥ 7.0%), and by CGM device type.Our data suggest that a 12-15-day period of monitoring every 3 months may be needed to optimally assess overall glucose control. Shorter periods of sampling can be useful, but the correlation with 3-month measures of glycemic control is lower.

Abstract

Identify factors predictive of severe hypoglycemia (SH) and assess the clinical utility of continuous glucose monitoring (CGM) to warn of impending SH.In a multicenter randomized clinical trial, 436 children and adults with type 1 diabetes were randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for SH were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon.The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were ≤ 70 mg/dL on the prior day (4.5 vs. 0.5%; P < 0.001), but the positive predictive value (PPV) was low (<5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM.SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day (P < 0.001), but the PPV is low.

Abstract

The evaluation of patient-reported outcomes (e.g. impact, satisfaction) is important in trials of continuous glucose monitoring (CGM). We evaluated psychometric properties of the CGM Satisfaction Scale (CGM-SAT) and the Glucose Monitoring Survey (GMS).CGM-SAT is a 44-item scale on which patients (n=224) or parents (n=102) rated their experience with CGM over the prior 6 months. GMS is a 22-item scale on which patients (n=447) or parents (n=221) rated the blood glucose monitoring system they were using (home glucose meter with or without CGM) at baseline and 6 months.The alpha coefficient for the CGM-SAT was > or = 0.94 for all respondents and for the GMS was > or = 0.84 for all respondents at baseline and 6 months. Parent-youth agreement was 0.52 for the CGM-SAT at 6 months and 0.24 and 0.20 for the GMS at baseline and 6 months for the Standard Care Group, respectively. Test-retest reliability of the GMS at 6 months for controls was r=0.76 for adult patients, 0.63 for pediatric patients, and 0.43 for parents. Factor analysis isolated measurement factors for the CGM-SAT labeled Benefits of CGM and Hassles of CGM, accounting for 33% and 9% of score variance, respectively. For the GMS, two factors emerged: Glucose Control and Social Complications, accounting for 28% and 9% of variance, respectively. Significant correlations of CGM-SAT with frequency of CGM use between 6 months and baseline and GMS with frequency of conventional daily self-monitoring of blood glucose at baseline support their convergent validity.The CGM-SAT and GMS are reliable and valid measures of patient-reported CGM outcomes.

Abstract

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) an important regulator of bone homeostasis, mediates its actions by binding to the vitamin D receptor (VDR), a nuclear transcription factor. Mutations in the VDR cause the rare genetic disease hereditary vitamin D resistant rickets (HVDRR). In this study, we examined two unrelated young female patients who exhibited severe early onset rickets, hypocalcemia, and hypophosphatemia. Both patients had partial alopecia but with different unusual patterns of scant hair. Sequencing of the VDR gene showed that both patients harbored the same unique nonsense mutation that resulted in a premature stop codon (R50X). Skin fibroblasts from patient #1 were devoid of VDR protein and 1,25(OH)2D3 treatment of these cells failed to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 action. In conclusion, we identified a novel nonsense mutation in the VDR gene in two patients with HVDRR and alopecia. The mutation truncates the VDR protein and causes 1,25(OH)2D3 resistance.

Abstract

The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes.This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subject's own baseline infusion rate. RESULTS Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted.The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.

Abstract

Insulin infusion pump therapy has dramatically improved over the past 20 years and can now address some of the specific challenges related to toddlers with diabetes. We discuss both the non-randomized and randomized controlled trials comparing continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) in this age group. There are advantages and disadvantages related to both CSII and MDI treatments, and ultimately the decision to use CSII should be individualized for each patient and family with the guidance of their diabetes team.

Abstract

This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing beta-cells in subjects with new-onset type 1 diabetes.A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test.One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly.Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.

Abstract

Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported.To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo.Multicenter, randomized, double-blind, placebo-controlled clinical trial.The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007.Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo.After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed.Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program.clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

Abstract

The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes.We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose.At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab.A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)

Abstract

Data on the relation between vitamin D status and body fat indexes in adolescence are lacking.The objective was to identify factors associated with vitamin D status and deficiency in obese adolescents to further evaluate the relation of body fat indexes to vitamin D status and deficiency.Data from 58 obese adolescents were obtained. Visceral adipose tissue (VAT) was measured by computed tomography. Dual-energy X-ray absorptiometry was used to measure total bone mineral content, bone mineral density, body fat mass (FM), and lean mass. Relative measures of body fat were calculated. Blood tests included measurements of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, type I collagen C-telopeptide, hormones, and metabolic factors. Vitamin D deficiency was defined as 25(OH)D < 20 ng/mL. PTH elevation was defined as PTH > 65 ng/mL.The mean (+/-SD) age of the adolescents was 14.9 +/- 1.4 y; 38 (66%) were female, and 8 (14%) were black. The mean (+/-SD) body mass index (in kg/m(2)) was 36 +/- 5, FM was 40.0 +/- 5.5%, and VAT was 12.4 +/- 4.3%. Seventeen of the adolescents were vitamin D deficient, but none had elevated PTH concentrations. Bone mineral content and bone mineral density were within 2 SDs of national standards. In a multivariate analysis, 25(OH)D decreased by 0.46 +/- 0.22 ng/mL per 1% increment in FM (beta +/- SE, P = 0.05), whereas PTH decreased by 0.78 +/- 0.29 pg/mL per 1% increment in VAT (P = 0.01).To the best of our knowledge, our results show for the first time that obese adolescents with 25(OH)D deficiency, but without elevated PTH concentrations, have a bone mass within the range of national standards (+/-2 SD). The findings provide initial evidence that the distribution of fat may be associated with vitamin D status, but this relation may be dependent on metabolic factors. This study was registered at www.clinicaltrials.gov as NCT00209482, NCT00120146.

Abstract

Despite a high incidence of nocturnal hypoglycemia documented by the use of continuous glucose monitoring (CGM), there are no reports in the literature of nocturnal hypoglycemic seizures while a patient is wearing a CGM device.In this article, we describe four such cases and assess the duration of nocturnal hypoglycemia before the seizure.In the cases where patients had a nocturnal hypoglycemic seizure while wearing a CGM device, sensor hypoglycemia (<60 mg/dl) was documented on the CGM record for 2.25-4 h before seizure activity.Even with a subcutaneous glucose lag of 18 min when compared with blood glucose measurements, glucose sensors have time to provide clinically meaningful alarms. Current nocturnal hypoglycemic alarms need to be improved, however, since patients can sleep through the current alarm systems.

Abstract

The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined.In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks.The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference.Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

Abstract

The purpose of this study was to determine whether, in a group of children with type 1 diabetes using insulin pump, a prebedtime snack with a relatively high fat content provides greater protection from nocturnal hypoglycemia than a snack containing the same amount of carbohydrate and protein but a lower fat content.Ten subjects, aged 6 to <18 yr, in a trial evaluating the Abbott Navigator glucose sensor, agreed to this ancillary study. On 12 or more separate nights, each subject was randomized by a Web site to a carbohydrate-low-fat (30 g CHO, 2.5 g protein, and 1.3 g fat; 138 kcal) snack or a carbohydrate-high-fat (30 g CHO, 2 g protein, and 20 g fat; 320 kcal) snack. Subjects used their usual evening snack algorithm to determine the size (in 15-g carbohydrate increments) and insulin dosage.Average glucose on 128 valid study nights before snack was similar in both groups. The proportion of nights with hypoglycemia (a sensor or meter glucose value or=200 mg/dL and at least 50 mg/dL above baseline, 35% high fat vs. 30% low fat).There were no statistical differences between the high- and low-fat snacks on the frequency of hyperglycemia or hypoglycemia. This study highlights the feasibility of web-based research in patients' home environment.

Abstract

Despite the standing of A1C as the most validated and widely used measure for average glycemic control over time, the relationship between A1C and glucose concentrations is not completely understood. The purpose of this Diabetes Research in Children Network (DirecNet) study was to use continuous glucose monitoring data to examine the relationship between A1C and glucose in type 1 diabetes.Forty-eight youth enrolled in studies of the Navigator continuous glucose monitor were encouraged to wear the Navigator sensor at home continuously. A1C was measured at baseline, at 3 months, and at 6 months. Sensor glucose data were directly transmitted via the Internet, assuring that essentially all glucose values were analyzed.Subjects had a median of 112 h/week of Navigator data in the first 3 months and 115 h/week in the second 3 months. The slope of mean glucose over the previous 3 months versus A1C was only 18 mg/dl per 1.0% A1C. Individually, there was substantial variation in the relationship between mean glucose and A1C. A1C was not associated with glucose lability after controlling for mean glucose. Measures of an individual's rate of glycation were moderately correlated at the 3- and 6-month visits.As the chemistry of glycation would predict, we found no evidence to contradict the simple hypothesis that A1C directly reflects mean glucose over time. There is, however, substantial variability in individual mean glucose concentrations for a given A1C. Transforming reliable A1C values into calculated mean glucose values would, when applied to an individual, introduce substantial error.

Abstract

African-American girls and women are at high risk of obesity and its associated morbidities. Few studies have tested obesity prevention strategies specifically designed for African-American girls. This report describes the design and baseline findings of the Stanford GEMS (Girls health Enrichment Multi-site Studies) trial to test the effect of a two-year community- and family-based intervention to reduce weight gain in low-income, pre-adolescent African-American girls.Randomized controlled trial with measurements scheduled in girls' homes at baseline, 6, 12, 18 and 24 month post-randomization.Low-income areas of Oakland, CA.Eight, nine and ten year old African-American girls and their parents/caregivers.Girls are randomized to a culturally-tailored after-school dance program and a home/family-based intervention to reduce screen media use versus an information-based community health education Active-Placebo Comparison intervention. Interventions last for 2 years for each participant.Change in body mass index over the two-year study.Recruitment and enrollment successfully produced a predominately low-socioeconomic status sample. Two-hundred sixty one (261) families were randomized. One girl per family is randomly chosen for the analysis sample. Randomization produced comparable experimental groups with only a few statistically significant differences. The sample had a mean body mass index (BMI) at the 74 th percentile on the 2000 CDC BMI reference, and one-third of the analysis sample had a BMI at the 95th percentile or above. Average fasting total cholesterol and LDL cholesterol were above NCEP thresholds for borderline high classifications. Girls averaged low levels of moderate to vigorous physical activity, more than 3 h per day of screen media use, and diets high in energy from fat.The Stanford GEMS trial is testing the benefits of culturally-tailored after-school dance and screen-time reduction interventions for obesity prevention in low-income, pre-adolescent African-American girls.

Abstract

To summarize the current literature on real-time continuous glucose monitors, focusing on devices that have been approved or are pending approval.Real-time continuous glucose sensors are new tools to assist in diabetes management. Several devices are currently being sold and additional monitors are expected to be available shortly. These sensors measure interstitial glucose - a distinct physiologic space when compared with the blood glucose. The ability to recognize trends in blood glucose levels provides a new paradigm for making insulin dose decisions and treating hypo- and hyperglycemia.Real-time continuous glucose monitoring systems are currently less accurate than home glucose meters, but provide information every 1-5 min throughout the day and night with alarms for hyper- and hypoglycemia, providing information on glucose trends and nocturnal glycemic excursions. Current real-time sensors are behavior modification tools. Thus, improvements in diabetes control depend on the willingness of patients to modify their diabetes management based on information provided by these devices.

Abstract

The glycemic patterns of children less than 7 years with type 1 diabetes have not been well studied using continuous glucose monitoring. Our goal was to assess the incidence of hypoglycemia as well as postprandial glycemic patterns in this age group utilizing continuous glucose monitoring.Nineteen children used the Medtronic MiniMed (Northridge, CA) CGMS System Gold on three to seven occasions over approximately 6 months.Nineteen children (nine girls and 10 boys; mean age 4.8 +/- 1.4 years, range 1.6-6.8 years) used the CGMS 102 times, providing 434 days of data; 79% of days were optimal based on CGMS Solutions software version 3.0. Mild hypoglycemia (glucose or=2 mg/dL/min following 50% of breakfasts. Children with hemoglobin A1c levels >or=8% had higher postprandial glucose concentrations. There was no significant advantage of continuous subcutaneous insulin infusion therapy over multiple daily injection therapy in decreasing postprandial hyperglycemia.CGMS tracings from young children with diabetes demonstrate frequent mild nocturnal hypoglycemia and significant postprandial hyperglycemia, with a rapid rise in glucose following the meal. The most rapid rate of rise and the most severe postprandial hyperglycemia occurred after breakfast.

Abstract

Control of hyperglycemia in adult medical and surgical intensive care units (ICUs) has been shown to dramatically decrease morbidity and mortality. Algorithms to achieve glycemic control in the ICU setting are evolving. We have evaluated the use of a discrete proportional-integral-derivative (PID) algorithm to control hyperglycemia in pediatric ICU (PICU) patients both with and without diabetes.Six PICU patients [four with diabetic ketoacidosis (DKA) and two with glucocorticoid-induced hyperglycemia] with glucose values >150 mg/dL were enrolled. Their hyperglycemia was managed with a PID algorithm that provided recommendations for both changes in the intravenous insulin infusion rate and the time to obtain the next discrete glucose value. Glucose targets were adjusted based on clinical circumstances.Patients (mean age 9.2 years; range 1.8-14 years) utilized the algorithm for a total of 454.4 h. Mean time to the initial glucose target was 8.7 h (range 1.3-15.1 h) in five patients. One subject with hyperosmolar DKA did not achieve target before discharge from the PICU, and another was at target when the algorithm was initiated. After the glucose target was achieved, the mean SD was 23.5 mg/dL, and glucose values were >40 mg/dL above target 13% of the time and <40 mg/dL below target 1% of the time. There were no glucose values <55 mg/dL.The PID algorithm safely and effectively controlled hyperglycemia in a PICU, despite multiple changes in intravenous fluids, steroid doses (including high-dose pulses), and hemodialysis.

Abstract

To evaluate the accuracy and precision of the FreeStyle Navigator continuous glucose monitoring system in children with type 1 diabetes.In 30 children with type 1 diabetes (mean age 11.2 +/- 4.1 years), the Navigator glucose values were compared with reference serum glucose values of blood samples obtained in an inpatient clinical research center and measured in a central laboratory using a hexokinase enzymatic method and in an outpatient setting with a FreeStyle meter. Median absolute difference (AD) and median relative absolute difference (RAD) were computed for sensor-reference and sensor-sensor pairs.The median AD and RAD were 17 mg/dl and 12%, respectively, for 1,811 inpatient sensor-reference pairs and 20 mg/dl and 14%, respectively, for 8,639 outpatient pairs. The median RAD between two simultaneous Navigator measurements (n = 1,971) was 13%. Ninety-one percent of sensors in the inpatient setting and 81% of sensors in the outpatient setting had a median RAD < or = 20%.The Navigator's accuracy does not yet approach the accuracy of current-generation home glucose meters, but it is sufficient to believe that the device has the potential to be an important adjunct to treatment of youth with type 1 diabetes.

Abstract

Strategies for preventing hypoglycemia during exercise in children with type 1 diabetes have not been well studied. The Diabetes Research in Children Network (DirecNet) Study Group conducted a study to determine whether stopping basal insulin could reduce the frequency of hypoglycemia occurring during exercise.Using a randomized crossover design, 49 children 8-17 years of age with type 1 diabetes on insulin pump therapy were studied during structured exercise sessions on 2 days. On day 1, basal insulin was stopped during exercise, and on day 2 it was continued. Each exercise session, performed from approximately 4:00-5:00 p.m., consisted of four 15-min treadmill cycles at a target heart rate of 140 bpm (interspersed with three 5-min rest breaks over 75 min), followed by a 45-min observation period. Frequently sampled glucose concentrations (measured in the DirecNet Central Laboratory) were measured before, during, and after the exercise.Hypoglycemia (< or = 70 mg/dl) during exercise occurred less frequently when the basal insulin was discontinued than when it was continued (16 vs. 43%; P = 0.003). Hyperglycemia (increase from baseline of > or = 20% to > or = 200 mg/dl) 45 min after the completion of exercise was more frequent without basal insulin (27 vs. 4%; P = 0.002). There were no cases of abnormal blood ketone levels.Discontinuing basal insulin during exercise is an effective strategy for reducing hypoglycemia in children with type 1 diabetes, but the risk of hyperglycemia is increased.

Abstract

We evaluated retrospectively plasma glucose levels and the degree of hypoglycemia, hyperglycemia, and glucose variability in a PICU and then assessed their association with hospital length of stay and mortality rates.Electronic medical records at the Packard Children's Hospital at Stanford University were reviewed retrospectively for all PICU admissions between March 1, 2003, and March 31, 2004. Patients with a known diagnosis of diabetes mellitus were excluded. The prevalence of hyperglycemia was defined with cutoff values of 110, 150, and 200 mg/dL. Hypoglycemia was defined as < or = 65 mg/dL. Glucose variability was assessed with a calculated glucose variability index.In 13 months, 1094 eligible admissions generated 18865 glucose values (median: 107 mg/dL; range: 13-1839 mg/dL). Patients in the highest maximal glucose quintile had a significantly longer median PICU length of stay, compared with those in the lowest quintile (7.5 days vs 1 day). Mortality rates increased as patients' maximal glucose levels increased, reaching 15.2% among patients with the greatest degree of hyperglycemia. Hypoglycemia was also prevalent, with 18.6% of patients (182 of 980 patients) having minimal glucose levels of < or = 65 mg/dL. There was an increased median PICU length of stay (9.5 days vs 1 day) associated with glucose values in the lowest minimal quintile, compared with those in the highest quintile. Hypoglycemia was correlated with mortality rates; 16.5% of patients with glucose levels of < or = 65 mg/dL died. Glucose variability also was associated with increased length of stay and mortality rates. In multivariate logistic regression analyses, glucose variability, taken with hyperglycemia and hypoglycemia, showed the strongest association with mortality rates.Hyperglycemia and hypoglycemia were prevalent in the PICU. Hypoglycemia, hyperglycemia, and, in particular, increased glucose variability were associated with increased morbidity (length of stay) and mortality rates.

Abstract

To compare and contrast proposed definitions of metabolic syndrome in pediatrics, and to determine prevalence of metabolic syndrome in preadolescent females when applying different criteria.A literature review on definitions of metabolic syndrome and cardiovascular "risk factor clustering" in children and adolescents published in the past decade. Pediatric definitions of metabolic syndrome were then applied to a community-based study of 261 black preadolescent females (Girls Health Enrichment MultiSite studies [GEMS]) and a school-based, cross-sectional study of 240 ethnically-diverse preadolescent females (Girls Activity, Movement and Environmental Strategy [GAMES]) who had a baseline physical examination and fasting morning blood sample.Agreement among pediatric definitions of metabolic syndrome was poor. The prevalence of MS and cardiovascular risk factor clustering ranged from 0.4% to 23.0% for GEMS and 2.0% to 24.6% for GAMES with definitions adapted from the National Cholesterol Education Program Adult Treatment Panel III, and 0% to 15.3% for GEMS and 0.4% to 15.8% for GAMES using modified criteria from the World Health Organization.The prevalence of metabolic syndrome in preadolescent girls varies widely because of disagreement among proposed definitions of metabolic syndrome in pediatrics. Further investigation is needed to determine which metabolic factors and their respective cut points should be used to identify children at risk for development of clinical disease.

Abstract

The optimal number/timing of calibrations entered into the CGMS (Medtronic MiniMed, Northridge, CA) continuous glucose monitoring system have not been previously described.Fifty subjects with Type 1 diabetes mellitus (10-18 years old) were hospitalized in a clinical research center for approximately 24 h on two separate days. CGMS and OneTouch Ultra meter (LifeScan, Milpitas, CA) data were obtained. The CGMS was retrospectively recalibrated using the Ultra data varying the number and timing of calibrations. Resulting CGMS values were compared against laboratory reference values.There was a modest improvement in accuracy with increasing number of calibrations. The median relative absolute deviation (RAD) was 14%, 15%, 13%, and 13% when using three, four, five, and seven calibration values, respectively (P < 0.001). Corresponding percentages of CGMS-reference pairs meeting the International Organisation for Standardisation criteria were 66%, 67%, 71%, and 72% (P < 0.001). Nighttime accuracy improved when daytime calibrations (pre-lunch and pre-dinner) were removed leaving only two calibrations at 9 p.m. and 6 a.m. (median difference, -2 vs. -9 mg/dL, P < 0.001; median RAD, 12% vs. 15%, P = 0.001). Accuracy was better on visits where the average absolute rate of glucose change at the times of calibration was lower. On visits with average absolute rates <0.5, 0.5 to <1.0, 1.0 to <1.5, and >or=1.5 mg/dL/min, median RAD values were 13% versus 14% versus 17% versus 19%, respectively (P = 0.05).Although accuracy is slightly improved with more calibrations, the timing of the calibrations appears more important. Modifying the algorithm to put less weight on daytime calibrations for nighttime values and calibrating during times of relative glucose stability may have greater impact on accuracy.

Abstract

To examine the effect of exercise on overnight hypoglycemia in children with type 1 diabetes mellitus (T1DM).At 5 clinical sites, 50 subjects with T1DM (age 11 to 17 years) were studied in a clinical research center on 2 separate days. One day included an afternoon exercise session on a treadmill. On both days, frequently sampled blood glucose levels were measured at the DirecNet central laboratory. Insulin doses were similar on both days.During exercise, plasma glucose levels fell in almost all subjects; 11 (22%) developed hypoglycemia. Mean glucose level from 10 pm to 6 am was lower on the exercise day than on the sedentary day (131 vs 154 mg/dL; P=.003). Hypoglycemia developed overnight more often on the exercise nights than on the sedentary nights (P=.009), occurring on the exercise night only in 13 (26%), on the sedentary night only in 3 (6%), on both nights in 11 (22%), and on neither night in 23 (46%). Hypoglycemia was unusual on the sedentary night if the pre-bedtime snack glucose level was>130 mg/dL.These findings indicate that overnight hypoglycemia after exercise is common in children with T1DM and support the importance of modifying diabetes management after afternoon exercise to reduce the risk of hypoglycemia.

Abstract

The objective of this study was to assess how the accuracy of the FreeStyle Flash (Abbott Diabetes Care, Alameda, CA) meter compares with that of the One Touch Ultra (Lifescan, Milpitas, CA) home glucose meter (HGM).Fifty children with type 1 diabetes (T1D), 10-17 years old, were admitted for two separate 24-h periods to assess the effect of exercise on subsequent nocturnal hypoglycemia. Resulting data were used in a preplanned analysis of the accuracy of the Ultra and FreeStyle HGMs. Glucose levels were measured throughout the day and night and every 15-20 min during a standardized exercise protocol. Reference samples were assayed in a central laboratory using a hexokinase enzymatic method. These reference glucose measurements were paired with HGM values from venous blood obtained within +/- 5 min.The median relative absolute difference was 5% for both the Ultra and FreeStyle HGMs, and the percentages of pairs meeting the International Organisation for Standardization criteria were 99% and 98%, respectively. The FreeStyle tended to read slightly higher than the reference method (median difference = +3 mg/dL; P < 0.001), and there was trend in this direction for the Ultra (median difference = +2 mg/dL, P = 0.15). Sensitivities for detection of hypoglycemia (reference < or = 60 and HGM < or = 70 mg/dL) were 96% and 100% for the Ultra and FreeStyle, respectively, and corresponding false-positive rates were both 5%.In a controlled clinical setting using venous blood samples, both the Ultra and FreeStyle meters demonstrated a high degree of accuracy compared with the laboratory reference over a broad range of glucose concentrations in children with T1D.

Abstract

A continuous glucose monitor satisfaction scale (CGM-SAT) was evaluated during a 6-month randomized controlled trial of the GlucoWatch G2 Biographer (GW2B) in youths with type 1 diabetes.At the end of the 6-month trial, 97 parents and 66 older children who had been randomized to the GW2B group completed the CGM-SAT, which assesses satisfaction on 37 items using a five-point Likert scale. Descriptive analysis, calculation of several reliability estimates, and assessment of concurrent validity were performed.The CGM-SAT demonstrated high internal reliability (Cronbach's alpha = 0.95 for parents and 0.94 for youths aged > or = 11 years), split-half reliability (rho = 0.91 for parents and 0.93 for youths), and parent-adolescent agreement (rho = 0.68, P < 0.001). Convergent validity was supported by marginally significant associations with treatment adherence and frequency of GW2B use. CGM-SAT scores did not correlate significantly with changes in treatment adherence, quality of life, or diabetes-related anxiety from baseline to 6 months. Mean scores on CGM-SAT items indicated that 81% of parental responses and 73% of youths' responses were less favorable than "neutral." Descriptive analysis indicated the GW2B requires substantial improvement before it can achieve widespread clinical utility and acceptance.The results supported the psychometric properties of the CGM-SAT. The CGM-SAT warrants further research use and cross-validation with other continuous glucose monitors. This study provides a benchmark for comparison with new glucose sensors.

A brief review of the use and utility of growth hormone stimulation testing in the NCGS: Do we need to do provocative GH testing?18th Annual National Cooperative Growth Study/5th Annual National Cooperative Somatropin Surveillance Investigator MeetingWilson, D. M., Frane, J.CHURCHILL LIVINGSTONE.2005: S21–S25

Abstract

True growth hormone deficiency (GHD) in childhood, while rare, has major clinical consequences. GHD is often associated with other pituitary hormone deficiencies, so these children may require multiple hormonal replacement and close clinical follow-up to optimize their outcome. Growth hormone stimulation testing (GHST), as currently conducted, is not a reliable diagnostic tool. Both changes in growth hormone assay methodologies and increases in the diagnostic threshold contribute to the incorrect labeling of a substantial proportion of normal children as having idiopathic GHD. Fortunately, newer imaging technologies and laboratory tests form a more rational basis to diagnose true GHD. The use of GHST among GH-naive subjects (<20 years of age) enrolled in the National Cooperative Growth Study has declined over the past two decades, from a high of 89% between 1987 and 1989 to only 52% in 2002. Given that GH stimulation testing does not meaningfully aid in distinguishing those few children with true growth hormone deficiency from the much more common short normal child and that alternatives are now available, it is time to discontinue the routine use of GHST in children.

Abstract

The objective of this study was to determine how subjects responded to alarms for hypo- and hyperglycemia while they were sleeping.Twenty subjects with type 1 diabetes (4-17 years old) were admitted to a clinical research center for approximately 24 h. Each subject wore two GlucoWatch G2 Biographers (GW2B) (Cygnus, Inc., Redwood City, CA) and was videotaped using an infrared camera from 9 p.m. to 7 a.m. The videotapes were reviewed to determine if the GW2B alarms were audible on the tape and to document the subject's response to the alarms. Because many alarms can occur surrounding a change in blood glucose, GW2B alarm "events" are defined as a one or more alarms separated from previous alarms by more than 30 min.Downloaded data from the biographers identified 240 individual alarms, 75% of which occurred while the subject was sleeping. Of the 240 alarms 68% were audible on the videotape. Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects 4-6 years old responded to 17% of alarms, 7-11 year olds responded to 20% of alarms, adolescents responded to 53% of alarms, and parents responded to 37% of alarms. Subjects awoke to 40% of the first alarm during the night, but to only 28% of subsequent alarms. There were 11 events when the glucose was confirmed to be < or = 70 mg/dL, and in each case the subject was awoken. Fifty-five percent of alarm events occurred when there was no hypo- or hyperglycemia confirmed by a reference glucose value.Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects awoke during all alarm events when hypoglycemia was confirmed, but there was a high incidence of false alarms.

Abstract

This study assesses whether use of the GlucoWatch G2 Biographer (GW2B) in addition to standard glucose monitoring lowers HbA(1c) and reduces hypoglycemia compared with standard glucose monitoring alone.In all, 200 subjects aged 7 to <18 years with type 1 diabetes were randomly assigned at five centers to standard glucose monitoring (usual care) or standard glucose monitoring plus GW2B use for 6 months. Study outcomes included HbA(1c) values obtained at 6 months and occurrence of severe hypoglycemia.The mean HbA(1c) at baseline was 8.0% in both groups; at 6 months, HbA(1c) was 7.9% in the usual care group and 8.1% in the GW2B group (95% CI for mean reduction in the GW2B group compared with the usual care group -0.4 to 0.1%; P = 0.15). A decrease in HbA(1c) of > or =0.5% was achieved in 21% of the usual care group and 28% of the GW2B group (P = 0.29). Severe hypoglycemia events occurred in 7% of the GW2B group and in 2% of the usual care group (P = 0.10). In the GW2B group, sensor use declined throughout the study from a mean value of 2.1 times/week in the 1st month to 1.5 times/week in the 6th month. Reasons given for declining use included skin irritation (76%), frequent skips (56%), excessive alarms (47%), and inaccurate readings (33%).Use of the GW2B in addition to standard glucose monitoring did not improve glycemic control or reduce the frequency of severe hypoglycemia. Skin reactions and other problems led to decreasing sensor use over time.

Abstract

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) high-performance liquid chromatography (HPLC) method for measuring hemoglobin A1c (HbA1c) serves as a reference standard against which other assays are compared. The DCA 2000 + Analyzer (Bayer Inc., Tarrytown, NY, USA), which uses an immunoassay, is a very popular device for measuring HbA1c levels in pediatric diabetes practices.To determine how HbA1c values measured with the DCA 2000 in a multisite, pediatric diabetes clinic setting compare with corresponding HbA1c values measured in the DCCT/EDIC laboratory.To examine this question, the Diabetes Research in Children Network (DirecNet) used the DCA 2000 in five clinical centers to measure baseline HbA1c levels in 200 youth with type 1 diabetes mellitus (T1DM) (aged 12.5 +/- 2.8 yr) who were participating in an outpatient clinical trial. At the same visit, an additional blood sample was obtained, refrigerated, and shipped to the DCCT/EDIC central laboratory for determination of HbA1c values.The central laboratory HbA1c value averaged 8.0 +/- 0.9% (mean +/- SD), with a median (25th and 75th quartiles) of 7.8% (7.3 and 8.5%, respectively). The DCA 2000 HbA1c values were strongly correlated (r = 0.94, p < 0.001), but significantly higher than DCCT/EDIC central laboratory values with a mean difference of +0.2% (95% confidence interval +0.14 to 0.23%, p < 0.001). There was some variation in the differences between DCA 2000 and central laboratory values at the five clinical centers (p < 0.001) with mean differences ranging between 0.0 and 0.3%, but differences between the two methods did not vary significantly by age or gender.Measurements of HbA1c by the DCA 2000 compare favorably with the DCCT/EDIC central laboratory method, albeit with slightly higher values.

Abstract

We previously reported the results of an inpatient accuracy study in children with type 1 diabetes using the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA). During the course of that study, a new process was implemented for manufacturing the CGMS sensor. Accuracy from the resulting modified sensor used by only 14 children was significantly better than the original version [median relative absolute difference (RAD), 11% vs. 19%; P < 0.001]. Baseline data from a subsequent outpatient study provide an opportunity to further assess the accuracy of the modified sensor in a much larger sample of children with type 1 diabetes.As part of a randomized trial to assess the utility of the GlucoWatch G2 Biographer (Cygnus, Inc., Redwood City, CA), 200 children with type 1 diabetes were instructed to wear a CGMS for 48-72 h in an outpatient setting at baseline. Glucose measurements from a OneTouch UltraSmart (Lifescan, Inc., Milpitas, CA) home glucose meter were downloaded and used as reference values to calculate accuracy measures.The overall median RAD was 12%. Accuracy was better during hyperglycemia than during hypoglycemia (median RAD, 10% vs. 20%; P < 0.001) and on optimal versus non-optimal days but did not vary significantly by the number of calibrations entered.These data confirm the improved accuracy previously reported for the modified version of the CGMS sensor.

Abstract

Our goals were to determine if continuous subcutaneous insulin infusion (CSII), compared with those continuing multiple daily injections (MDIs), can be safely used in young children, if those on CSII will have superior glycemic control, if subjects using CSII will have less hypoglycemia for their level of control, and if families using CSII will report an improved quality of life.We conducted a randomized 1-year feasibility trial comparing CSII with continuing MDIs in preschool children with a history of type 1 diabetes for at least 6 months' duration. Prospective outcomes included measures of overall glycemic control (HbA1c and continuous glucose monitoring system), the incidence of severe hypoglycemia and diabetic ketoacidosis, the percent of glucose values below 3.9 mmol/l, and the parents' report of quality of life.The 19 subjects' ages ranged from 1.7 to 6.1 (mean 3.6) years, duration of diabetes ranged from 0.6 to 2.6 (mean 1.4) years, and baseline HbA1c ranged from 6.7 to 9.6% (mean 7.9%). Seven subjects were male. Nine subjects were randomized to start CSII and 10 to continue on MDI. All baseline characteristics were well balanced. Overall metabolic control, diabetes quality of life, and the incidence of hypoglycemia were similar in the two groups. No subject had diabetic ketoacidosis, while one subject in each group had an episode of severe hypoglycemia. No CSII subject discontinued using the pump during or after the study.CSII can be a safe and effective method to deliver insulin in young children.

Abstract

The GlucoWatch G2 Biographer (GW2B) (Cygnus, Inc., Redwood City, CA) provides near-continuous monitoring of glucose values in near real time. This device is equipped with two types of alarms to detect hypoglycemia. The hypoglycemia alarm is triggered when the current glucose measurement falls below the level set by the user. The "down alert" alarm is triggered when extrapolation of the current glucose trend anticipates hypoglycemia to occur within the next 20 min.We used data from an inpatient accuracy study to assess the performance of these alarms. During a 24-h clinical research center stay, 89 children and adolescents with Type 1 diabetes mellitus (3.5-17.7 years old) wore 174 GW2B devices and had frequent serum glucose determinations during the day and night.Sensitivity to detect hypoglycemia (reference glucose < or = 60 mg/dL) during an insulin-induced hypoglycemia test was 24% with the hypoglycemia alarm alone and 88% when combined with the down alert alarm. Overnight sensitivity from 11 p.m. to 6 a.m. was 23% with the hypoglycemia alarm alone and 77% when combined with the down alert alarm. For 16% of hypoglycemia alarms, the reference glucose was above 70 mg/dL for 30 min before and after the time of the alarm. For the two alarm types combined, the corresponding false-positive rate increased to 62%.The down alert alarm substantially improves the sensitivity of the GW2B to detect hypoglycemia at the price of a large increase in the false alarm rate. The utility of these alarms in the day-to-day management of children with diabetes remains to be determined.

Abstract

Hyperinsulinemia/insulin resistance is a risk factor for future type 2 diabetes. Fasting insulin and blood lipids serve as direct indicators of subsequent risk and as biochemical markers of metabolically significant adiposity. We examined the feasibility of obtaining fasting blood samples and report correlates of these biochemical markers in an understudied population sample.Fasting samples were requested from African-American girls, 8.00 to 10.99 years of age, for insulin, glucose, and lipid concentrations. Indices of insulin sensitivity and secretion were calculated and correlated with anthropometric, dietary, physical activity, and body composition data.Samples were obtained from 119 of 210 (57%) girls, varying from 5% to 86% across the four field centers. Glucose ranged from 71 to 104 mg/dL. Eleven percent had insulin concentrations >20 mU/liter. One girl had a triglyceride concentration >130 mg/dL. Thirteen percent had total cholesterol >200 mg/dL, whereas all subjects had high-density lipoprotein (HDL)-cholesterol of > or =35 mg/dL. Fourteen percent had low-density lipoprotein levels >130 mg/dL. Insulin concentrations showed consistently strong associations with measures of body weight (rs = 0.54 to 0.67); glucose, HDL, and LDL showed weaker correlations (rs = -0.11 to 0.22). Insulin concentration was highly correlated with indices of both insulin secretion and resistance (rs = 0.99).Fasting blood samples in young African-American girls were obtained with reasonable cooperation in three of the four field centers involved in this community-based study. Fasting insulin, glucose, LDL, and HDL concentrations may help evaluate future diabetes and cardiovascular risk in children of this age.

Abstract

To describe associations between sexual maturation and body composition in a sample of African-American girls who were participants in phase 1 pilot interventions of the Girls Health Enrichment Multisite Studies.Stature, weight, and waist circumference were measured. Pubic hair and breast development were assessed, and body composition was measured by DXA for 147 African-American girls who were 8 to 10 years of age from three field centers. Participants had BMI > or =25th percentile for age (one site) or BMI > or =50th percentile for age.Girls Health Enrichment Multisite Studies girls had greater BMI, fat mass, and percentage body fat than national norms and relatively earlier initiation of breast development and pubic hair. Increasing stages of breast development, but not stages of pubic hair, were related to increased stature, waist circumference, BMI, lean mass, fat mass, and percentage of body fat. Pubescent girls (breast stage > or = 2) were greater than six times as likely to be classified as at risk of overweight (BMI > or = 85th percentile) and greater than eight times as likely to be classified as overweight (BMI > or = 95th percentile) as prepubescent counterparts. Adjusted odds ratios for advanced breast development [breast stage > or = 2 (8 years) or > or = 3 (9 and 10 years)] were 3.6 for risk of overweight and for overweight compared to girls with average or less than average breast development.Sexual maturation is important to consider in understanding the classification of overweight and the development of obesity during adolescence. Breast development and pubic hair development should be considered separately for their associations with growth and body composition.

Abstract

Despite more than 40 years of pediatric growth hormone (GH) replacement, we are still limited in our ability to make a definitive diagnosis of GH deficiency (GHD) in children. Historically, GH stimulation tests (GHSTs) have been used to discriminate between GHD and idiopathic short stature. Over the years, increases in the peak diagnostic GH cutoffs and the proliferation of GH assays have fundamentally changed the nature of the GHST. In our opinion, today's GHSTs lack reproducibility and accuracy, are expensive, and can be dangerous. Moreover, newer diagnostic tools, such as high-resolution neuroimaging, measurements of serum insulin-like growth factor 1 and insulin-like growth factor-binding protein 3, and an increasing number of genetic tests, have emerged. We believe that it is no longer appropriate to use GHSTs to diagnose childhood GHD. Instead, diagnosis should be based on a combination of auxological, biochemical, neuroradiological and genetic considerations. Here, we examine the alternatives to the GHST that are currently available and literature that supports their use. We believe that these alternative methods should replace the GHST.

Abstract

The diagnosis of growth hormone deficiency (GHD) historically has relied on measurement of growth hormone (GH) concentrations following stimulation, usually with a non-physiologic provocative agent. Despite the use of more specific GH assays, the peak concentration of GH below which a child is considered GH deficient has risen. We examine the pitfalls associated with GH stimulation tests, specifically, the lack of reliability and accuracy of these tests, and their inability to predict who will benefit from GH therapy. We recommend that GH stimulation tests no longer routinely be used for the diagnosis of GHD in children.

Abstract

Glargine (Lantus) is a recently approved, long-acting insulin analog that is increasingly being used in children with diabetes. The aim of this retrospective chart review was to summarize our experience in starting glargine in children and adolescents with diabetes. SUBJECTS AND STUDY METHODS: We reviewed the medical records of 71 children with type 1 diabetes (29 boys and 42 girls) who initiated glargine therapy to improve glycemic control between 1 June 2001 and 30 June 2002. Data were collected for 6 months before and 6 months after adding glargine.Subjects' mean age [+/-standard deviation (SD)] at diagnosis of diabetes was 7.5 +/- 4.1 yr. Mean age at initiation of glargine therapy was 11.5 +/- 4.9 yr. The total daily long-acting insulin dose decreased by about 20% after initiating glargine therapy. There were no significant differences in hemoglobin A1c (HbA1c) and blood glucose control prior to and after initiating glargine therapy (HbA1c at baseline 8.9 +/- 1.6% and HbA1c after 6 months of glargine therapy was 8.9 +/- 1.5%). Overall, blood glucose concentrations did not differ significantly throughout the study. Patients who switched to glargine because of nocturnal hypoglycemia had a 65% decrease in nocturnal blood glucose reading less than 50 mg/dL. There were three seizures in the first week after initiating glargine therapy.This retrospective study suggests that glargine is at least as effective as other long-acting insulins but that care must be taken during the conversion process to avoid hypoglycemia.

Abstract

The workup of hypoglycemia requires frequent glucose sampling. We designed these studies to determine if the Continuous Glucose Monitoring System (CGMS) and the GlucoWatch G2 Biographer (GW2B) are sufficiently accurate to use in nondiabetic children. Study design Fifteen healthy children (aged 9-17 years, 11 boys) wore a GW2B and a CGMS during a 24-hour period, and reference serum glucose was measured hourly during the day and half-hourly overnight.Compared with the reference glucose, the median absolute difference in concentrations measured by the GW2B (487 pairs) was 13 mg/dL, and the difference measured by the CGMS was 17 mg/dL (668 pairs), with 30% and 42% of values using the GW2B and CGMS, respectively, deviating >20 mg/dL from the reference value. The GW2B reported values <60 mg/dL in 73% of subjects, the CGMS in 60% of subjects. In none of these episodes was serum glucose truly low. Spurious high glucose concentrations also were observed with the sensors. The mean reference glucose was lowest at 5 am (89 mg/dL) and highest at 11:30 pm (106 mg/dL) during the 24-hour period.Neither the CGMS nor the GW2B is accurate enough to establish population standards of the glycemic profile of healthy children and cannot be recommended in the workup of hypoglycemia in nondiabetic youth.

Abstract

The goal of this study was to assess the accuracy of the GlucoWatch G2 Biographer (GW2B) and the continuous glucose monitoring system (CGMS) during hypoglycemia in children and adolescents with type 1 diabetes.During a 24-h clinical research center stay, 91 children and adolescents with type 1 diabetes (aged 3.5-17.7 years) wore one or two CGMSs, and 89 of these subjects wore one or two GW2Bs. Frequent serum glucose determinations were made during the day, overnight, and during insulin-induced hypoglycemia resulting in 192 GW2B reference pairs and 401 CGMS reference pairs during hypoglycemia (reference glucose < or =60 mg/dl).During hypoglycemia, the median absolute difference between the 192 GW2B reference glucose pairs was 26 mg/dl and between the 401 CGMS reference glucose pairs was 19 mg/dl with 31 and 42%, respectively, of the sensor values within 15 mg/dl of the reference glucose. Sensitivity to detect hypoglycemia when the GW2B alarm level was set to 60 mg/dl was 23% with a false-alarm rate of 51%. Analyses suggested that modified CGMS sensors that became available in November 2002 might be more accurate than the original CGMS sensors (median absolute difference 15 vs. 20 mg/dl).These data show that the GW2B and the CGMS do not reliably detect hypoglycemia. Both of these devices perform better at higher glucose levels, suggesting they may be more useful in reducing HbA1c levels than in detecting hypoglycemia.

Abstract

Anecdotal reports suggest that the addition of a gonadotropin releasing hormone (GnRH) analog (GnRHa) in addition to L-thyroxine (LT4) replacement may increase adult stature in children with severe longstanding hypothyroidism by prolonging the pubertal growth period. This retrospective chart review compares the height outcome and body mass index in 33 children (21 treated with LT4 alone and 12 treated with LT4 + GnRHa) with severe longstanding hypothyroidism and bone age delay. Seventeen controls and six GnRHa-treated patients were followed to adult height (BA >14 yr [F]/16 yr [M] and/or growth velocity < 2 cm/yr). At diagnosis, GnRHa-treated patients were 1) older and shorter for chronological age, and 2) more advanced in puberty and bone age. Despite these differences, at adult height, both groups had similar improvements in height Z scores, similar height deficits, and comparable adult heights. Changes in BMI Z score were similar for both groups. Our study suggests that the addition of GnRHa to LT4 may improve interval growth without imposing a risk of obesity in children with longstanding severe hypothyroidism.

Abstract

Detection and prevention of nocturnal hypoglycemia is a major medical concern at diabetes camps.We conducted an open-label trial of the Cygnus GlucoWatch biographer to detect nocturnal hypoglycemia in a diabetes camp, a nonclinical environment with multiple activities.Forty-five campers (7-17 years old) wore a biographer. The biographer was placed on the arm at 6:00 PM, with the low alarm set to 85 mg/dL (4.7 mmol/L). Overnight glucose monitoring occurred per usual camp protocol. Counselors were to check and record blood glucose values if the biographer alarmed.Biographers were worn for 154 nights by 45 campers. After a 3-hour warm-up period, 67% of biographers were calibrated, of which 28% were worn the entire night (12 hours). Thirty-four percent of readings were skipped because of: "data errors" (65%), sweat (20%), and temperature change (16%). Reported biographer values correlated with meter glucose values measured 11 to 20 minutes later (r = 0.90). Of 20 low-glucose alarms with corresponding meter values measured within 20 minutes, there were 10 true-positive alarms, 10 false-positive alarms, and no false-negative alarms. Campers reported sleep disruption 32% of the nights, and 74% found the biographer helpful. Campers reported they would wear the biographer 4 to 5 nights each week.Half of the biographer low-glucose alarms that had corresponding blood meter values were true-positive alarms, and the remaining were false-positive alarms. There was close correlation between the biographer and meter glucose values. The majority of campers found the biographer helpful and would use it at home.

A multicenter study of the accuracy of the One Touch Ultra home glucose meter in children with type 1 diabetes.Diabetes technology & therapeutics2003; 5 (6): 933-941

Abstract

Data are not readily available on the accuracy of one of the most commonly used home blood glucose meters, the One Touch Ultra (LifeScan, Milpitas, California). The purpose of this report is to provide information on the accuracy of this home glucose meter in children with type 1 diabetes. During a 24-h clinical research center stay, the accuracy of the Ultra meter was assessed in 91 children, 3-17 years old, with type 1 diabetes by comparing the Ultra glucose values with concurrent reference serum glucose values measured in a central laboratory. The Pearson correlation between the 2,068 paired Ultra and reference values was 0.97, with the median relative absolute difference being 6%. Ninety-four percent of all Ultra values (96% of venous and 84% of capillary samples) met the proposed International Organisation for Standardisation (ISO) standard for instruments used for self-monitoring of glucose when compared with venous reference values. Ninety-nine percent of values were in zones A + B of the Modified Error Grid. A high degree of accuracy was seen across the full range of glucose values. For 353 data points during an insulin-induced hypoglycemia test, the Ultra meter was found to have accuracy that was comparable to concurrently used benchmark instruments (Beckman, YSI, or i-STAT); 95% and 96% of readings from the Ultra meter and the benchmark instruments met the proposed ISO criteria, respectively. These results confirm that the One Touch Ultra meter provides accurate glucose measurements for both hypoglycemia and hyperglycemia in children with type 1 diabetes.

The accuracy of the CGMS in children with type 1 diabetes: results of the diabetes research in children network (DirecNet) accuracy study.Diabetes technology & therapeutics2003; 5 (5): 781-789

Abstract

The accuracy of the Continuous Glucose Monitoring System, CGMS (Medtronic MiniMed, Northridge, CA) was assessed in children and adolescents with type 1 diabetes mellitus (T1DM) when compared with reference serum glucose levels during spontaneous fluctuations in glucose levels over 24 h and during acute hyper- and hypoglycemia. Ninety-one subjects with type 1 diabetes (3.5-17.7 years old) wore one or two CGMSs while blood samples were obtained for serum glucose determinations (made at a central laboratory) hourly during the day, every 30 min overnight, and every 5 min during meal-induced hyperglycemia and insulin-induced hypoglycemia tests, resulting in 6778 CGMS-reference glucose pairs. CGMS function was assessed on each of the 3 days of sensor life. The median relative absolute difference (RAD) between the CGMS and reference values was 18% (25th, 75th percentiles = 8%, 34%). Similar results were obtained on each of the 3 days of sensor life. Accuracy was worse during hypoglycemia than during hyperglycemia. Modified sensors that first became available in November 2002 were more accurate than were the original sensors (median RAD = 11% vs. 19%) and had better precision (r = 0.92 vs. r = 0.77) during time periods in which two CGMSs were simultaneously used. The CGMS sensors that have been in clinical use until recently are often inaccurate in quantifying glucose values in children with T1DM. However, recent modifications to the sensor have resulted in substantially better accuracy and reliability. This improved function, if confirmed by additional data, may enhance the clinical utility of the CGMS.

Abstract

It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes.In a randomized, controlled, nonblinded clinical trial, we screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet-cell antibodies; 3152 tested positive; 2103 of the 3152 underwent genetic, immunologic, and metabolic staging to quantify their risk; 372 of the 2103 had a projected five-year risk of more than 50 percent; 339 of the 372 (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low-dose subcutaneous ultralente insulin, administered twice daily for a total dose of 0.25 unit per kilogram of body weight per day, plus annual four-day continuous intravenous infusions of insulin. Oral glucose-tolerance tests were performed every six months. Median follow-up was 3.7 years. The primary end point was a diagnosis of diabetes.Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in the observation group. The cumulative incidence of diabetes was similar in the two groups (relative risk in the intervention group as compared with the observation group, 0.96). Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal base-line glucose tolerance (22 percent per year) than among those with normal base-line glucose tolerance (10 percent per year, P<0.001). There were no episodes of severe hypoglycemia. The incidence of chemical hypoglycemia, assessed without ascertainment bias, was similar in the two groups.In persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes.

Abstract

The 61st Annual Meeting and Scientific Sessions of the American Diabetes Association (ADA) in Philadelphia, PA, (June 22-26, 2001) presented many topics of interest to pediatric clinicians. Of particular interest were the results of the insulin injection arm of the Diabetes Prevention Trial for type 1 diabetes mellitus (DM) (DPT-1). Over 80,000 relatives of patients with type 1 DM were screened. Ultimately, 339 subjects were randomized either to active therapy (twice daily insulin injections plus an annual insulin infusion) or to close observation. Risk prediction algorithms appeared to be accurate. Unfortunately, however, insulin therapy did not decrease the risk of developing DM. Of note, this was primarily a pediatric study with most of those randomized under 21 years of age. As expected, young subjects (<12 years) progressed toward the development of DM at a faster rate than older subjects (>15 years). The second arm of the DPT-1 trial, testing oral insulin in those with intermediate risk (25-50%) for DM, is still recruiting subjects. The controversial topic of continuous subcutaneous insulin infusion (CSII) in young children was also addressed. Many investigators presented data strongly supporting the successful use of infusion pumps in young children. In general, glycemic control was improved or remained stable, the incidence of severe hypoglycemia was low, and families reported more flexibility in their lifestyle. Obesity, an increasing problem in pediatric patients, was also addressed.

Abstract

Microvascular abnormalities are associated with and causative of the development of end-stage organ complications in adult diabetic patients. Whether the same microvascular abnormalities are present in pediatric patients is not known and has not been studied because of a lack of real-time technology, methodology to study young patients, and availability of an appropriate noninvasive site for in vivo studies. We hypothesized that microvascular abnormalities should be present in pediatric patients despite their young age and the relatively short durations of the disease. In this study, computer-assisted intravital microscopy (CAIM) was adapted to blindly quantify microvascular abnormalities in 12 pediatric type 1 diabetic mellitus (T1DM) patients (ages = 6-16 years; mean +/- SD = 11.42 +/- 3.42; duration since diagnosis = 2-14 years; mean +/- SD = 6.75 +/- 3.79) in vivo, using the microcirculation of the bulbar conjunctiva as a noninvasive site. Microvascular abnormalities, commonly found in adult patients, existed in the conjunctival microcirculation of all pediatric T1DM patients in varying degrees despite their relatively young age. A severity index (SI) was developed to reflect the cumulative severity of the microvascular abnormalities and was computed as the summation of all microvascular abnormalities found in each patient. SI for the 12 T1DM patients (mean +/- SD = 7.42 +/- 1.88; median = 8; mode = 9) differed significantly from that for the nondiabetic controls (mean +/- SD = 0.67 +/- 0.78; median = 0.5; mode = 0; P < 0.0001). In addition, SI correlated with hemoglobin A1c levels (mean +/- SD = 9.18 +/- 1.57) of T1DM patients but did not correlate with the duration of disease since diagnosis of the same patients. This observation raises the possibility that diabetic pathogenesis may precede the onset of overt disease or clinical diagnosis. This study confirms that CAIM may represent the availability of a useful real-time technology to study conjunctival microvascular abnormalities in vascular diseases in juvenile as well as adult patients.

Abstract

In cord blood and late gestation maternal serum, IGF-I is positively correlated with birth weight, whereas IGF-binding protein-1 (IGFBP-1) is inversely correlated with birth weight. Our goal was to determine whether maternal serum or amniotic fluid concentrations of IGF-I, IGFBP-1, or nonphosphorylated IGFBP-1 (npIGFBP-1) in early gestation predict later fetal growth abnormalities. Maternal serum was collected prospectively across gestation (5-40 wk) from 749 pregnant subjects. Amniotic fluid was collected after amniocentesis during wk 15-26 from 207 subjects. We compared median serum concentrations of IGF-I, IGFBP-1, and npIGFBP-1 in 38 subjects who delivered growth-restricted infants with the control group of 236 subjects with normal weight infants for each gestational age grouping, wk 5-12, 13-23, and 24-34. In the control group median IGF-I concentrations were 14.8, 11, and 15.6 nmol/liter for wk 5-12, 13-23, and 24-34, respectively, compared with 13.7, 14.3, and 10.6 nmol/liter in the intrauterine growth restriction (IUGR) group. Median IGFBP-1 concentrations were 8.5, 30.4, and 24.4 nmol/liter, respectively, in controls, compared with 11.4, 28.6, and 25.5 nmol/liter in the IUGR group. Median npIGFBP-1 concentrations were 6.9, 22, and 17.4 nmol/liter, respectively, in controls, compared with 5.0, 32.1, and 24.2 nmol/liter in the IUGR group. In the control group the median amniotic fluid IGFBP-1 level was 13,160 nmol/liter, and the median npIGFBP-1 level was 15,970 nmol/liter; in the IUGR group these levels were 13,440 and 18,440 nmol/liter, respectively. No clinically useful differences were found between the IUGR and control groups. Our results do not support the use of maternal serum IGF-I or IGFBP-1 or amniotic fluid IGFBP-1 or npIGFBP-1 early in gestation to predict later fetal growth restriction.

Abstract

To find the time of the serum gonadotropin peak after depot leuprolide injection in children and to show that depot leuprolide therapy can be monitored by measuring serum luteinizing hormone (LH) immediately after injections.We measured concentrations of leuprolide, LH, and follicle-stimulating hormone (FSH) at multiple time points before and after the first dose of depot leuprolide in 14 pubertal children beginning therapy. Gonadotropins and sex steroids were measured again after the fourth dose.Serum leuprolide, LH, and FSH levels rose rapidly after initial injection, reaching sustained elevations at 30 to 120 minutes. The median LH level increased from 2.1 mIU/mL at baseline to a peak of 27.5 mIU/mL at 45 minutes, and FSH increased from 5.2 to 16.5 mIU/mL. After 3 months on therapy, median serum LH after depot leuprolide injection was only 0.83 mIU/mL, similar to levels observed after intravenous or subcutaneous gonadotropin-releasing hormone stimulation in comparable subjects on depot leuprolide.Our pharmacokinetic data demonstrate that free leuprolide present in a depot leuprolide injection is equivalent to gonadotropin-releasing hormone in stimulating a rapid rise in serum gonadotropin concentrations. We propose that a single serum sample for LH obtained 30 to 60 minutes after depot leuprolide injection in children provides a convenient and accurate assessment of treatment efficacy.

Abstract

Intensive diabetes management requires frequent home glucose monitoring, multiple daily insulin injections or chronic subcutaneous insulin infusion, and adjustments of insulin doses in response to changes in blood glucose levels, food intake, and exercise. It also requires a periodic review of previous glucose results to recognize patterns of hyper- or hypoglycemia. The goals of intensive management are age dependent. In young children, avoidance of severe hypoglycemia is the major goal. In older children and adolescents, lowering hemoglobin A(1c) becomes an increasingly important goal. In children of all ages, the ability to have a flexible lifestyle and meal plan is often a priority. This article provides a brief overview of the rationale for implementing intensive diabetes management in pediatric patients, and practical guidelines for implementation.

Abstract

Type 1 diabetes begins with the progressive autoimmune mediated destruction of the insulin-producing beta cells. When sufficient beta cell function is lost, the endocrine phase, characterized by insulin deficiency and hyperglycemia, supervenes. While a genetic predisposition to diabetes is an important precondition, most believe an environmental factor or factors serve as the trigger for initiating this process. In this paper we review trials designed to prevent or delay the clinical onset of diabetes. In these studies, high-risk individuals are identified by their genetic predisposition to diabetes, and/or by the presence of immune markers indicating activation of the autoimmune process directed against islet cells. The Deutsche Nicotinamide Intervention Study (DENIS) randomized 55 high-risk subjects to either nicotinamide or placebo and found no significant benefit. The European Nicotinamide Diabetes Intervention Trial (ENDIT) completed enrollment in May 1998. ENDIT screened over 40 000 relatives, randomizing 552 to either nicotinamide or placebo. Results are expected in May of 2003. Designed to test if avoidance of cow's milk in infancy will decrease the incidence of diabetes, the Trial to Reduce Type I Diabetes in the Genetically at Risk (TRIGR). High-risk infants are randomly assigned to different supplemental formulas in the first 6 months of life. Initial results suggest that removing cow's milk has a protective effect. The ongoing, NIH funded, multicenter Diabetes Prevention Trial-Type 1 (DPT-1) is testing two antigen-based (insulin) interventions in relatives at high risk for diabetes. Now in its sixth year, the DPT-1 study group has screened over 84,000 individuals. As of November 2000, 339 subjects have been randomized in the parenteral insulin study, completing the enrollment phase. Enrollment continues in the oral insulin study. Results of this trial are not yet available. Different epitopes of insulin and its analogs, monoclonal antibodies, and cytokine-based therapy, among others, have all been proposed as potential new interventional agents. While a great deal of effort will be required to test these approaches, the potential benefits of prevention justify these research efforts.

Abstract

To determine the relationship between first-phase (1 minute + 3 minutes) insulin production during the intravenous glucose tolerance test (IV-GTT) and risk factors for developing type 1 diabetes.Relatives of persons with type 1 diabetes (n = 59,600) were screened for islet cell antibodies (ICAs). Subjects who had positive screening results underwent IV-GTT (> or =2 times), repeat ICA screening, insulin autoantibody (IAA) screening twice, and an oral glucose tolerance test.Of the 59,600 subjects in the study, 2199 (3.69%) had positive findings on initial ICA test. IV-GTTs were performed in 1622 subjects, with children <8 years having the lowest first-phase insulin release (FPIR) and subjects 8 to 20 years of age having the highest FPIR. The FPIR was lower for subjects with a confirmed positive ICA test result or a positive IAA test result, subjects with higher titers of ICA or IAA, and subjects who had an abnormal (impaired or diabetic) oral glucose tolerance test result.FPIR in the IV-GTT correlates strongly with risk factors for development of type 1 diabetes.

Abstract

This review summarizes seven trials of growth hormone (GH) treatment for X-linked hypophosphatemic rickets (XLHR). These trials range in size from 5 to 30 patients; but despite the limited number of patients enrolled, they represent the largest studies to date of growth hormone in this disorder. Conventional treatment in XLHR, oral phosphate and calcitriol, is often unable to normalize serum phosphate concentration fully and many patients fail to reach normal adult height. The studies reviewed report increased growth velocity when exogenous GH is added to conventional therapy, although the independent effect of GH is difficult to evaluate. Younger patients appear to respond better to GH than do older patients. Disproportionate growth of the trunk may be a problem. Some patients with XLHR have received GH for more than 6 years, yet little is known about the impact of GH on adult height. Reported increases in phosphate concentrations following GH in XLHR are of uncertain clinical benefit. While GH appears to be safe in XLHR, long-term benefits remain unclear.

Abstract

The authors discuss the usability of an automated tool that supports entry, by clinical experts, of the knowledge necessary for forming high-level concepts and patterns from raw time-oriented clinical data.Based on their previous work on the RESUME system for forming high-level concepts from raw time-oriented clinical data, the authors designed a graphical knowledge acquisition (KA) tool that acquires the knowledge required by RESUME. This tool was designed using Protégé, a general framework and set of tools for the construction of knowledge-based systems. The usability of the KA tool was evaluated by three expert physicians and three knowledge engineers in three domains-the monitoring of children's growth, the care of patients with diabetes, and protocol-based care in oncology and in experimental therapy for AIDS. The study evaluated the usability of the KA tool for the entry of previously elicited knowledge.The authors recorded the time required to understand the methodology and the KA tool and to enter the knowledge; they examined the subjects' qualitative comments; and they compared the output abstractions with benchmark abstractions computed from the same data and a version of the same knowledge entered manually by RESUME experts.Understanding RESUME required 6 to 20 hours (median, 15 to 20 hours); learning to use the KA tool required 2 to 6 hours (median, 3 to 4 hours). Entry times for physicians varied by domain-2 to 20 hours for growth monitoring (median, 3 hours), 6 and 12 hours for diabetes care, and 5 to 60 hours for protocol-based care (median, 10 hours). An increase in speed of up to 25 times (median, 3 times) was demonstrated for all participants when the KA process was repeated. On their first attempt at using the tool to enter the knowledge, the knowledge engineers recorded entry times similar to those of the expert physicians' second attempt at entering the same knowledge. In all cases RESUME, using knowledge entered by means of the KA tool, generated abstractions that were almost identical to those generated using the same knowledge entered manually.The authors demonstrate that the KA tool is usable and effective for expert physicians and knowledge engineers to enter clinical temporal-abstraction knowledge and that the resulting knowledge bases are as valid as those produced by manual entry.

Regular monitoring of bone age is not useful in children treated with growth hormone12th Annual National Cooperative Growth Study Investigators MeetingWilson, D. M.AMER ACAD PEDIATRICS.1999: 1036–39

Abstract

Although bone age estimates are traditionally used to monitor children receiving growth hormone therapy, few data support this practice. Bone age determination is fraught with technical difficulties, resulting in high interobserver differences. Longitudinal studies show that an individual's bone age can change erratically over time. The resulting errors in predicted adult heights based on these bone age determinations are large. Moreover, growth hormone therapy appears to accelerate bone maturation. The radiographic evidence of this acceleration can be delayed. In this setting, improvements in predicted adult heights can be artifactually large. Routine monitoring of bone age during GH therapy is unnecessary. Bayley and Pinneau, bone age determination, Greulich and Pyle, predicted height, radiography, Tanner and Whitehouse.

Abstract

Quantitative ultrasound is the newest noninvasive method to be accepted for assessing bone mineral in adults. Heel ultrasound measurements correlate with bone density measurements by dual X-ray absorptiometry (DXA) and predict fracture risk in adults. Far less is known about the value of calcaneus ultrasound (CUS) in children. We determine spine, femoral neck, and whole-body bone mineral by DXA and heel bone mass by CUS in 125 youths (69 females, 56 males) ages 9-25 yr. CUS and DXA measurements of bone mass increased with age and pubertal development during adolescence in a parallel fashion. Among females, Tanner stage was a stronger predictor than age for all CUS and DXA measurements, and among males, pubertal stage was a stronger predictor for spine bone mineral apparent density (BMAD) and femoral bone mineral density (BMD). CUS measurements correlated moderately well with DXA measurements of the spine, femoral neck, and whole-body BMD and spine BMAD (r = 0.23-0.58, p < 0. 008). CUS warrants further study as a tool for assessing bone mineral acquisition in children.

Abstract

Risk factors for the initiation of cigarette smoking were examined in 2 consecutive cohorts of teenagers (N = 1,901). Students in Cohort 1 were followed over 4 years from 9th to 12th grade; those in Cohort 2 were followed over 3 years from 9th to 11th grade. Among girls with no history of smoking at baseline, those with more friends who smoked at baseline (p < .001) and those with higher sociability scores (p < .05) were significantly more likely to have tried smoking over the study interval. Among boys with no history of smoking at baseline, those with more friends who smoked at baseline (p < .05) and those with higher depression symptoms scores (p < .01) were significantly more likely to have tried smoking over the study interval. The data suggest that future research is needed to examine potential gender differences that may have implications for the next generation of smoking-prevention programs.

Abstract

This study prospectively evaluated the relationship between early puberty and the onset of internalizing symptoms and disorders in adolescent girls.The sample was drawn from 1,463 sixth-, seventh-, and eighth-grade girls who participated in a longitudinal school-based study of growth and development. Pubertal stage was determined by self-assessment of Tanner stage. Psychiatric assessments included self-report instruments and structured diagnostic interviews. Survival methods were utilized for data analysis.Girls with onset of internalizing symptoms were on average 5 months earlier in pubertal development than those who were asymptomatic (p < .001). In addition, girls with earlier maturation (earliest quartile) were more likely to develop internalizing symptoms than were nonearly matures (hazard ratio = 1.8, confidence interval = 1.2, 2.7). In a subsample of girls followed into high school, early-maturing girls were at marginally higher risk (p < .10) for developing internalizing disorders by the study's end. The highest risk for internalizing disorders was for those girls with both early puberty and prior internalizing symptoms (odds ratio = 3.3).Early puberty increases the risk of internalizing symptoms and perhaps internalizing disorders in adolescent girls.

Abstract

Packy & Marlon, an interactive video game designed to improve self-care among children and adolescents with diabetes, was evaluated in a six-month randomized controlled trial. In the game, players take the role of animated characters who manage their diabetes by monitoring blood glucose, taking insulin injections, and choosing foods, while setting out to save a diabetes summer camp from marauding rats and mice who have stolen the diabetes supplies. Study participants were patients aged 8 to 16 from two separate diabetes clinics. Each participant received a Super Nintendo video game system at an initial clinic visit and was randomly assigned to receive either Packy & Marlon (treatment group, N = 31) or an entertainment video game containing no diabetes-related content (control group, N = 28). Participants were interviewed and a parent filled out a questionnaire at baseline, three months, and six months. The findings in this study indicate that well-designed, educational video games can be effective interventions. There was improvement in the treatment group relative to the control group in terms of diabetes-related self-efficacy (p = 0.07), communication with parents about diabetes (p = 0.025), and self-care behaviours (p = 0.003), and a decrease in unscheduled urgent doctor visits (p = 0.08). There were no significant differences between the groups in knowledge about diabetes or in glycated haemoglobin (HbA1c) levels. Since participants in the study were in general well-controlled patients who were receiving excellent medical care, future research is contemplated involving youngsters who are not under good glycaemic control.

Abstract

The authors examined factors prospectively associated with age of onset of partial syndrome eating disorders over a 4-year interval in a community sample (N = 877) of high school-age adolescent girls. Four percent developed a partial syndrome eating disorder over the interval. A measure of weight concerns was significantly associated with onset in a multivariate Cox proportional hazard analysis (p < .001). Girls scoring in the highest quartile on the measure of weight concerns had the highest incidence (10%) of partial syndrome onset, whereas none of the girls in the lowest quartile developed eating disorder symptoms. This finding is consistent with both theoretical and clinical perspectives and may represent a useful step toward the establishment of a rational basis for the choice of a prevention intervention target.

Abstract

We report results of a prospective examination of the influence of outcome expectancy variables and inherited temperaments on the onset of drinking over a 12-month period in a sample of 1,164 high school students. While univariate prospective analysis indicated that drinkers and nondrinkers were different both on measures of outcome expectancy and temperament, multivariate analysis supported, most strongly, a social learning account of the processes influencing the onset and maintenance of drinking behavior in this sample. The multivariate analysis revealed that only expectancies for enhanced social behavior were consistently associated with the onset of drinking from baseline to 12-month follow-up (p < .001). Among all nondrinkers at baseline, those entertaining higher expectancies about the positive effects of alcohol on social interaction were more likely to begin drinking between baseline and follow-up. At present, few, if any, alcohol abuse prevention studies with adolescents have explicitly attempted to alter alcohol expectancies or to establish a link between expectancy and behavior change. Our results suggest that it may be useful to do so.

Abstract

We compared a rapid, subcutaneous (SQ), single-sample gonadotropin-releasing hormone (GnRH) stimulation test with the standard multiple-sample, intravenous (IV) GnRH stimulation test used in the evaluation of central precocious puberty (CPP).We evaluated 22 patients presenting with evidence of precocious puberty. GnRH (100 microg) was administered subcutaneously in the clinic setting with single serum luteinizing hormone (LH) measured 40 minutes after injection. A standard IV GnRH stimulation test was performed within 2 weeks, with serum LH obtained at 0, 20, 40, and 60 minutes. LH was assayed by immunochemiluminometric assay.The mean peak LH levels after IV and SQ testing were identical. A significant correlation (r = .88) was found between the LH determined by SQ stimulations and the peak LH determined by IV GnRH testing. CPP was diagnosed (LH, >/- 8 IU/L) by both SQ and IV testing in 7 of 22 patients and was excluded by both tests in 14 of 22 patients. A diagnostic discrepancy between peak IV and SQ results was seen in 1 patient.We conclude that mean GnRH-stimulated LH levels from rapid SQ and standard IV testing are indistinguishable and that individual LH levels by each method are strongly correlated. A rapid SQ GnRH test is a valid tool for laboratory confirmation of CPP.

Abstract

Osteoarthritis is a disease in which articular cartilage metabolism is altered, leading to cartilage destruction. As insulin-like growth factor-I (IGF-I) is the major anabolic mediator for articular cartilage, and the IGF-binding proteins (IGFBPs) are an integral part of the IGF axis, they may play a role in the pathophysiology of osteoarthritis. Chondrocytes isolated from fibrillated and normal appearing areas of osteoarthritic human cartilage and from normal cartilage were studied for IGF and IGFBP expression. IGF and IGFBP messenger ribonucleic acids were analyzed by a RT-quantitative PCR technique and Northern blotting. In osteoarthritic chondrocytes, IGF-I message was increased 3.5-fold, IGFBP-3 was increased 24-fold, and IGFBP-5 was increased 16-fold over normal chondrocytes. Chondrocytes from normal appearing areas of cartilage from osteoarthritic joints had intermediate levels. Message levels for beta-actin, IGF-II, and IGFBP-4 were unchanged between the cartilage types. IGF and IGFBP production were analyzed by Western ligand blots and RIAs of conditioned medium from cartilage cultured in serum-free conditions. IGF-I was undetectable in conditioned medium from normal cartilage and increased in that from osteoarthritic cartilage. Osteoarthritic cartilage samples produced IGFBP-2, -3, and -4; glycosylated IGFBP-4; and IGFBP-5. IGFBP-2, -3, and -5 production was increased in osteoarthritic cartilage. Proteases with activity against IGFBP-3 and -5 were also produced by osteoarthritic cartilage. The observation that IGFBP-3 and -5 expression and production are elevated in osteoarthritic cartilage suggests that they may be acting as a competitor for IGF-I in osteoarthritic cartilage, thus reducing the anabolic stimulation of this tissue and contributing to the net loss of cartilage in this disease.

Abstract

The question of if testing for growth hormone release is necessary in patients with chronic renal failure (CRF) is part of a greater debate. The question of what constitutes growth hormone deficiency (GHD) has become more controversial over the past few years. In some ways, the question has been replaced by the question, "Who will have a meaningful response to growth hormone (GH) therapy?" Since children with CRF generally respond to GH therapy, the question should be recast as, "When is testing for growth hormone release necessary in patients with CRF?" Why is the diagnosis of GHD important? A clear diagnosis of class GHD has many important implications for a patient. GHD is an easily treated cause of neonatal hypoglycemia. The diagnosis alerts the clinician to search for etiologies of GHD such as intracranial tumors and should stimulate a search for other pituitary deficiencies. Another important claim is that patients with classic GHD have a better long-term response to GH therapy. Children in other diagnostic categories, such as renal failure and Turner syndrome, also respond to GH therapy. Do diagnostic studies use to determine the function of the growth hormone-insulin-like growth factor (GH-IGF) axis help in the management of these children? Recently, experts have become increasingly interested in what constitutes a useful diagnostic test. To be a "good" diagnostic test, a procedure should have the following properties: (1.) have a rational connection to the disorder; (2.) good concordance with the diagnosis/outcome; (3.) accurate; and (4.) reproducible. Among tests that share these properties, the best test is generally the easiest and/or the least expensive. Many different tests can be used to evaluate the GH-IGF axis. These include GH stimulation tests, 24-hour GH profiles, IGF-I, and insulin-like growth factor binding protein 3 (IGFBP-3). High quality determinations of IGF-I and IGFBP-3 can be used to evaluate the GH-IGF axis.

Abstract

Male adolescents with constitutional delay of growth and puberty may have significant psychosocial difficulties related to their sexual immaturity and short stature. The purpose of this study was to test the hypothesis that 1 year of oxandrolone therapy would increase growth velocity and thereby improve psychosocial functioning in boys with constitutional delay of growth and pubertal development.Forty boys (ages 11 to 14.7 years) with delayed pubertal development and short stature were recruited from the pediatric endocrine clinics of 14 medical centers. The boys were randomized using a block design stratified for age to receive either oxandrolone (0.1 mg/kg daily for 1 year) or an identical-appearing placebo tablet, using a double-masked design.Growth velocity in the oxandrolone-treated boys was significantly greater than in the control boys (9.5 vs 6.8 cm/y). Likewise, the mean height SD score increased 0.41 in the oxandrolone group, whereas it decreased 0.03 in the control group. Those in the oxandrolone group gained 2.4 kg more than those in the placebo group. Mean predicted adult heights did not change in either group. The mean rates of pubertal progression were equivalent in both groups. Self-image (Piers-Harris Self Concept Scale) and social competence (Child Behavior Profile) were normal at baseline in both groups and did not change significantly over the course of the study in either group. No complications of oxandrolone therapy were identified.This randomized, placebo-controlled trial demonstrates that low-dose oxandrolone can increase both height and weight velocity in boys with delayed puberty safely. Under the conditions of this study, however, the increased growth velocity in the oxandrolone-treated boys was not associated with a greater improvement in psychosocial status compared with the control boys.

Abstract

IGF-I is the major anabolic factor for cartilage matrix production. Chondrocytes and cartilage treated with interleukin-1 alpha (IL-1 alpha), and chondrocytes from several models of inflammatory joint disease, exhibit reduced responsiveness to IGF-I. Since the IGF-binding proteins (IGFBPs) modulate the effects of IGF-I, we examined the effect of IL-1 alpha and tumor necrosis factor-alpha (TNF-alpha) on IGFBP production by normal human articular chondrocytes in primary culture. Western ligand blots and immunoprecipitation of conditioned medium samples showed that articular chondrocytes produced IGFBPs-2, -3 and -4 and glycosylated IGFBP-4. Both IL-1 alpha and TNF-alpha increased chondrocyte production of IGFBP-3, but did not alter IGFBP-4 production. The activity of a neutral metalloprotease with the ability to cleave IGFBP-3 was also increased by IL-1 alpha. These data suggest that the cytokines IL-1 alpha and TNF-alpha may act to reduce IGF-I access to chondrocytes by increasing production of IGFBP-3. This may be a factor in the decreased matrix production in the inflammatory arthritides.

Abstract

We assessed the utility of spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays in the evaluation and monitoring of precocious puberty.We evaluated serum gonadotropin values from intravenous GnRH stimulation tests in 49 girls with clinical signs suggesting central precocious puberty (CPP). Because GnRH-stimulated LH has been considered the standard for diagnosing CPP, we used it as the basis for comparison with GnRH-stimulated FSH levels and spontaneous LH and FSH measured by immunochemiluminometric assay.Twenty-six patients had a peak serum LH value above the +2 SD threshold for normal prepubertal female subjects (LH > 5 IU/L). The GnRH-stimulated FSH values had a narrow range and did not discriminate patients with CPP. In contrast, elevations in spontaneous LH and FSH were found to be specific for CPP. Spontaneous LH levels correlated strongly with peak stimulated LH levels in subjects with precocious puberty (r = 0.79) or in control subjects (r = 0.93, both p (0.0001). Spontaneous LH levels in excess of 0.1 IU/L detected true puberty with 94% sensitivity and 88% specificity. Random LH levels in excess of 0.3 IU/L had 100% specificity for CPP.The GnRH-stimulated FSH levels do not adequately differentiate children with and without CPP and have limited utility in the evaluation of precocious puberty. Spontaneous FSH levels are elevated in CPP with fair sensitivity and marked specificity. Elevated random LH, measured by third-generation assay such as immunochemiluminometric assay, is strongly correlated with and highly predictive of elevated peak GnRH-stimulated LH, and is a useful screening tool for CPP.

Abstract

We sought to establish normative data for spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays (ICMA) in children and adolescents.Random serum samples were obtained from 375 normal subjects (0.1 to 17.7 years, 230 female subjects). Intravenous GnRH stimulation tests were performed in 41 normal subjects (4.8 to 18 years, 20 female subjects). Normal ranges were calculated by age and Tanner stage. Immunochemiluminometric assays of LH and FSH concentrations were compared with levels obtained by a sensitive immunofluorometric assay and a less sensitive radioimmunoassay.Random gonadotropin concentrations in normal children followed the pattern of transient elevation in infancy, low but measurable prepubertal levels, and markedly increased values at puberty. Spontaneous LH levels were higher in male infants but were not statistically different in boys and girls after infancy. Mean prepubertal LH was 0.04 +/- 0.04 IU/L (n = 66), rising 100-fold during puberty. Spontaneous FSH levels were much higher than LH values, were higher in female infants, and rose threefold at puberty. Peak GnRH-stimulated LH was identical in prepubertal boys and girls (1.8 +/- 1.3 IU/L, n = 17) and increased 20-fold at puberty. Mean peak GnRH-stimulated FSH was highest in prepubertal female subjects. Luteinizing hormone values measured by ICMA and immunofluorometric assay were highly correlated, but radioimmunoassay levels diverged markedly from ICMA levels at lower concentrations. Because absolute levels were higher, FSH values correlated adequately in the three assays throughout the normal physiologic range.Measurement of LH by ICMA is much more sensitive than older assay methods. Spontaneous LH can be accurately measured by ICMA to the very low levels present in normal prepubertal children, providing a potentially important biochemical discriminator of pubertal status. An ICMA GnRH-stimulated LH level greater than 5 IU/L is suggestive of maturing gonadotropin secretion. The ICMA LH assays provide significant enhancement in sensitivity; these assays should be used when levels may be low, and by their accuracy may reduce the time and expense of testing procedures.

Abstract

The quantification of messenger RNA is central in studies of gene expression. We describe a quantitative assay for specific mRNAs (QASM) that measures mRNAs for insulin-like growth factor-I, IGF binding proteins (IGFBPs) -2, -3, -4, and -5, and beta-actin. The assay utilizes reverse transcription and polymerase chain reaction, followed by an ELISA based DNA assay technique. The use of internal (competitive) quantification standards gave poorly linear results, while external standards gave linear and reproducible results. QASM results correlated with IGFBP protein concentrations in conditioned medium and with mRNA levels determined by Northern blotting. QASM was used to study IGFBP expression in human malignant melanoma cells. Messenger RNA for IGFBP-2, -3, and -5 were present, while IGF-I and IGFBP-4 mRNAs were not detected. IGFBP-2 and -3 expression was increased in a dose dependent manner by treatment with IGF-I. Protein concentrations in conditioned media paralleled mRNA levels. QASM is a sensitive, specific, and reproducible approach to determining mRNA levels.

Abstract

This review discusses normal growth patterns and the appropriate use of preprinted growth curves. The important roles of thyroid and growth hormone in the modulation of growth are delineated. I present an approach to the evaluation and proper management of children and adolescents with short stature and poor growth.

Abstract

Community-based prospective studies are needed to shed light on mechanisms that may influence development of eating disorders and identify variables that could serve as potential targets for prevention efforts. In this paper we examine level of weight preoccupation and other variables prospectively associated with age of onset of eating disorder symptoms over a 3-year interval in a community sample (N = 939) of young adolescent girls. 3.6% (32/887) experienced onset of symptoms over the interval. Only one factor, a measure of Weight Concerns, was significantly associated with onset (p < .001). Girls scoring in the highest quartile on the measure of Weight Concerns had the shortest survival time (12% incidence by age 14.5) and those scoring in the lowest quartile had the highest survival time (2% incidence by age 14.5; p < .001). This finding is consistent with both theoretical and clinical perspectives and represents one of the first prospective demonstrations of a linkage between weight and body shape concerns and later onset of eating disorder symptoms. An understanding of the independent variables that predispose girls to development of symptoms is a useful step towards the establishment of a rational basis for the choice of a prevention intervention target.

Abstract

To test the hypothesis that the patterns of pubertal progression, early vs late puberty and fast vs slow, are associated with the age at which girls start to drink alcohol and smoke cigarettes.The study included 1463 female students, 10.7 to 18.2 years of age, who were assessed five times during the 2.7-year study. Data regarding pubertal stage, alcohol use, and cigarette use were obtained at each assessment. These data were used to calculate two indexes of pubertal development, the age at which the midpoint of puberty was achieved and the rate of progression through puberty, and the ages when each subject first drank, first drank moderate amounts of alcohol, and first smoked.Girls with earlier puberty (midpoint < 12.2 years) first reported drinking any alcohol at a median age of 12.5 years, 0.7 years younger than girls whose puberty was later. Similarly, girls with earlier puberty reported drinking moderate amounts of alcohol at a median age of 13.7 years, 0.9 years younger than girls with later puberty. Girls with earlier puberty further reported first smoking cigarettes at a median age of 12.8 years, 0.6 years younger than girls with later puberty. The rate of pubertal progression was significantly associated only with the age when girls first drank moderate amounts of alcohol.Earlier puberty is associated with a younger age of onset for both drinking and smoking among adolescent girls.

Abstract

Nine hundred thirty-nine 6th and 7th grade girls participated in the baseline phase of a prospective study designed to examine a set of potential risk factors for the development of eating disorders. Of the 939,839 girls (89%) completed the bulimia nervosa section of the Structured Clinical Interview for DSM-III-R disorders. One girl received the diagnosis of bulimia nervosa, another 35 were classified as a symptomatic group. Using analysis of covariance (ANCOVA), controlling for age and stage of sexual maturation, symptomatic and asymptomatic groups were compared on the following measures: Eating Disorders Inventory (EDI), BMI, triceps skinfold thickness, waist-to-hip ratio, depression symptoms (CES-D and DSRS), Restraint Scale, and a measure of family adaptability and cohesion (FACES). Symptomatic girls were more developmentally mature, significantly heavier, reported greater fear of weight gain, experienced greater dysphoria, indicated increased body dissatisfaction, and reported greater feelings of inadequacy and personal worthlessness. Their status on these dimensions may indicate potential vulnerability to eating disorders and, ultimately, suggest the choice of targets for intervention. Our future goal is to conduct the prospective analyses needed to confirm the hypothesized linkages.

Abstract

Linear growth results from proliferation and differentiation of chondrocytes within the growth plates and is regulated, in part, by the insulin-like growth factors (IGFs). IGF binding proteins (IGFBPs) also appear to play a significant, but yet unclear, role. To examine IGFBP production by chondrocytes, we isolated bovine chondrocytes from adult articular, fetal articular, and fetal growth plate cartilage, and maintained them in primary culture as high-density monolayers or encapsulated in alginate beads. Cells were cultured in serum-free conditions with human GH (hGH), insulin, hIGF-I, or hIGF-II. Human IGF-I resulted in higher DNA content in all three of the chondrocyte types. Conditioned medium samples were analyzed for IGFBPs by Western ligand blotting. Chondrocytes released IGFBPs of 24, 29, 33, 39, and 43 kilodaltons (kDa). Deglycosylation and immunoblotting identified the 39/43-kDa doublet as IGFBP-3 and the 33-kDa band as IGFBP-2. All chondrocyte types released 29- and 24-kDa IGFBP bands constitutively. Adult articular chondrocytes increased production all IGFBPs in response to IGF-I, but particularly the 29-kDa band (17-fold increase). Fetal articular chondrocytes showed a similar pattern, but with less of an increase when treated with IGF-I. Fetal growth plate chondrocytes primarily showed increases in IGFBP-3 and the 24-kDa form (4.7- and 2.7-fold, respectively) in response to IGF-I. Although the role of IGFBPs in IGF mediation of articular and growth plate chondrocyte metabolism requires further research, we show here that bovine chondrocytes produce IGFBPs, and the IGFs regulate this production.

Abstract

This is the first long-term, controlled study evaluating the effectiveness of a prevention curriculum designed to modify the eating attitudes and unhealthful weight regulation practices of young adolescent girls. Nine hundred sixty-seven sixth and seventh-grade girls were randomized to experimental healthy weight regulation curriculum or no-treatment control classes. A prevention intervention was developed around three principal components: (1) Instruction on the harmful effects of unhealthful weight regulation; (2) promotion of healthful weight regulation through the practice of sound nutrition and dietary principles and regular aerobic physical activity; (3) development of coping skills for resisting the diverse sociocultural influences that appear linked to the current popular obsessions with thinness and dieting. The intervention failed to achieve the hoped-for impact. We did observe a significant increase in knowledge among girls receiving the intervention and among high-risk students only, there was a small albeit statistically significant effect on body mass index. These findings question the wisdom of providing a curriculum directed at all young adolescents, most of whom are not at risk to develop an eating disorder. Rather than targeting the entire population, a healthy weight curriculum designed to modify the eating attitudes and unhealthful weight regulation practices of young adolescent girls might better focus on "at risk" students.

Abstract

To examine the relationships between hours of television viewing and adiposity and physical activity among female adolescents, a cohort study with follow-up assessments 7, 14, and 24 months after baseline was conducted. All sixth- and seventh-grade girls (N = 971) attending four northern California middle schools were eligible to participate. Six hundred seventy-one students had sufficient data for baseline cross-sectional analyses, and 279 students in a no-intervention cohort had sufficient data for longitudinal analyses. The baseline sample had a mean age of 12.4 years and was 43% white, 22% Asian, 21% Latino, 6% Pacific Islander, 4% black, 2% American Indian, and 2% other. Hours of after-school television viewing, level of physical activity, and stage of sexual maturation were assessed with self-report instruments. Height, weight, and triceps skinfold thickness were measured and body mass index (ratio of weight [in kilograms] to height [in meters] squared) and triceps skinfold thickness were adjusted by level of sexual maturity for the analyses. Baseline hours of after-school television viewing was not significantly associated with either baseline or longitudinal change in body mass index or triceps skinfold thickness. Baseline hours of after-school television viewing was weakly negatively associated with level of physical activity in cross-sectional analyses but not significantly associated with change in level of physical activity over time. All results were essentially unchanged when adjusted for age, race, parent education, and parent fatness. Among adolescent girls, television viewing time appears to have only weak, if any, meaningful associations with adiposity, physical activity, or change in either over time.

Abstract

Currently, many workers in the field of medical informatics realize the importance of knowledge reuse. The PROTEGE-II project seeks to develop and implement a domain-independent framework that allows system builders to create custom-tailored role-limiting methods from generic reusable components. These new role-limiting methods are used to create domain- and task-specific knowledge-acquisition tools with which an application expert can generate domain- and task-specific decision-support systems. One required set of reusable components embodies the problem-solving knowledge to generate temporal abstractions. Previously, members of the PROTEGE-II project have used these temporal-abstraction mechanisms to infer the presence of myelotoxicity in patients with AIDS. In this paper, we show that these mechanisms are reusable in the domain of assessment of children's growth.

Abstract

To test the usefulness of estrogen priming to enhance the growth hormone (GH) response following stimulation with clonidine hydrochloride in short children.Randomized and patient series.Pediatric endocrine clinic in a referral center.Seventy-three children (63% male) between 1.8 and 15.4 years of age (mean age, 8.8 years) with growth problems who underwent clonidine GH stimulation tests were randomly assigned to receive either estrogen pretreatment or no pretreatment. An additional 49 subjects, seen before or after the randomized study and who did not receive conjugated estrogen, are also described.Consecutive sample.Estrogen pretreatment consisted of 2.5 mg of conjugated estrogen (Premarin) to be taken the evening before and the morning of the clonidine GH stimulation test. Growth hormone concentrations were determined before and 60 and 90 minutes after the subjects received oral clonidine hydrochloride (5 micrograms/kg) by a laboratory blinded to the subject's estrogen status. Growth hormone concentrations greater than 10 micrograms/L were considered normal.Eight of the 73 subjects failed both clonidine and arginine-insulin GH stimulation tests. We analyzed the GH data from the 65 GH-sufficient subjects to determine the effect of estrogen pretreatment on the specificity of the clonidine GH stimulation test. There were no statistically significant differences in the mean GH concentrations between the two groups at any time point during the test.Our data demonstrate that estrogen priming does not improve the diagnostic yield of clonidine GH stimulation tests.

Abstract

Although biotechnology has provided physicians with essentially unlimited supplies of growth hormone (GH), there are currently only a few clear-cut indications for exogenous GH therapy. Data now support the use of GH in the treatment of children with GH deficiency and short girls with Turner syndrome. Tantalizing preliminary data suggest that GH therapy has a role in the management of short, poorly growing children with other causes for their growth failure. Recent studies have examined the utility of GH therapy in GH-deficient adults, whereas other studies suggest that GH improves the clinical status of GH-sufficient older adults. This article explores the recent data underlying these claims.

Abstract

Although the incidence of first panic attacks appears to peak during adolescence, little is known about which features of adolescence contribute to the risk of a first panic episode. The purpose of this study was to compare the relative importance of age and pubertal stage in explaining the occurrence of panic attacks in adolescents.From a school-based sample of sixth- and seventh-grade girls, 754 subjects completed both a structured clinical interview determining history of one or more panic episodes and a self-assessment of Tanner stages of pubertal development. A multiple logistic regression analysis was performed with panic attack history as the dependent variable and pubertal stage, age, and their interaction as the independent variables.A history of one or more four-symptom panic attacks was found in 5.3% of the girls (N = 40). After age was controlled for, pubertal stage was significantly related to panic attack history. At each age, higher rates of panic attacks were found in the more physically mature girls.Pubertal stage, after adjustment for the effects of age, appears to predict panic attack occurrence in young adolescent girls. Understanding the link between puberty and panic may offer clues regarding the onset and etiology of panic attacks.

Abstract

Forty patients with karyotypically proven Turner syndrome were prospectively studied using magnetic resonance imaging (MRI) and echocardiography in order to determine the frequency of cardiovascular anomalies and to assess the utility of both imaging modalities as methods for cardiovascular evaluation in Turner syndrome. Cardiovascular anomalies were found in 45% of patients. A high absolute prevalence of bicuspid aortic valve (17.5%) and aortic coarctation (12.5%) were observed relative to comparable series. Of clinically significant abnormalities, three of five aortic coarctations and four of five ascending aortic dilatations were solely MRI detected and not evident at echocardiographic examination. MRI is thus seen as a valuable adjunct to echocardiography in the cardiovascular evaluation of Turner syndrome patients. The usefulness of MRI primarily relates to its ability to provide excellent visualisation of the entire thoracic aorta where a large proportion of clinically significant anomalies occur in Turner syndrome.

Abstract

IGFBP-3 concentrations rise in the second decade of life. To test the hypothesis that the stage of pubertal development, independent of chronological age, was associated with these increases we measured serum IGFBP-3 concentrations by radioimmunoassay in 324 sixth and seventh grade girls (12.3 +/- 0.7 years) at the beginning of a multisite school-based health curriculum. The mean (+/- SD) serum IGFBP-3 among the 242 girls with complete data was 4.0 +/- 0.7 mg/l. Pubertal stage was significantly associated with IGFBP-3 (p less than 0.0001, ANOVA). Mean concentrations rose from 3.5 +/- 0.7 mg/l among those with the earliest pubertal stages to 4.2 +/- 0.7 mg/l among the mature girls. IGF-I and IGFBP-3 concentrations were significantly correlated (Spearman's r = 0.43, p less than 0.0001). After controlling for the association between pubertal development and IGFBP-3 concentrations, only the waist/hip ratio, among the various measures of body composition, was significantly associated with IGFBP-3 concentration (Spearman's r = -0.23, p = 0.0002). Likewise, none of the measures of nutrition: intake of total calories, protein, fat and carbohydrate; serum iron; red cell mean corpuscular volume; or cholesterol; were significantly associated with IGFBP-3 concentrations. There was, however, a small, but significant association between IGFBP-3 concentrations and both serum transferrin and blood hemoglobin concentrations. Pubertal stage has a significant impact on IGFBP-3 concentrations and those attempting to utilize IGFBP-3 concentrations during adolescence should be cognizant of the subject's pubertal stage.

Abstract

To examine the association between stage of sexual maturation and eating disorder symptoms in a community-based sample of adolescent girls.All sixth- and seventh-grade girls (N = 971) enrolled in four northern California middle schools. MAIN VARIABLES EXAMINED: Pubertal development measured using self-reported Tanner stage and body mass index (kg/m2). The section of the Structured Clinical Interview for DSM-III-R Disorders (SCID) discussing bulimia nervosa was used to evaluate symptoms of bulimia nervosa.Girls manifesting eating disorder symptoms, while not significantly older than their peers without such symptoms, were more developmentally advanced as determined with Tanner self-staging. The odds ratio for the association between sexual maturity and symptoms was 1.8 (95% confidence interval, 1.2 to 2.8); ie, at each age, an increase in sexual maturity of a single point was associated with a 1.8-fold increase in the odds of presenting symptoms. The odds ratio for the association between body mass index (adjusted for sexual maturity) and symptoms was 1.02 (95% confidence interval, 1.0 to 1.05). There was no independent effect of age or of the interaction between age and the sexual maturity index.These results suggest that (1) puberty may be a risk factor for the development of eating disorders, and (2) prevention efforts might best be directed at prepubertal and peripubertal adolescents.

Abstract

It has been shown previously that MCF-7 cells proliferate in response to nanomolar concentrations of IGF-I and IGF-II. It has also been reported that the actions of both peptides are mediated through the IGF-I receptor. To further characterize these observations, we used MCF-7 and Hs578T cell lines in the serum-free/phenol red-free system developed by Ogasawara and Sibarsku, 1988. Cell proliferation was studied in the presence of insulin, IGF-I and -II and a series of growth factor receptor antibodies. No effect was observed on Hs578T cell proliferation with any of the growth factors. However, MCF-7 cells were stimulated 4-5 fold with IGF-I and insulin, while IGF-II was only slightly less potent. alpha IR3, a monoclonal antibody directed against the IGF-I receptor, was stimulatory when added alone. However, alpha IR3 blocked approximately 50% of the IGF-I response, only 5% of the insulin response, and did not block the IGF-II effect on cell proliferation. These data suggest that alpha IR3 and IGF-I are acting as agonists through the IGF-I receptor, but that insulin and IGF-II are acting through other receptors. Two different IGF-II/M-6-P receptor antibodies and an insulin receptor antibody failed to significantly block IGF-II actions. All three antibodies were stimulatory when added alone. beta-gal inhibited 27% of the IGF-II response and had no effect when added alone. Since beta-gal decreases the binding affinity of the IGF-II/M-6-P receptor for IGF-II and does not bind to the IGF-I or insulin receptor, these data suggest the possibility that IGF-II mitogenic action is mediated through the IGF-II/M-6-P receptor. In summary, these data indicate that nanomolar concentration of insulin, IGF-I and IGF-II are potent mitogens in MCF-7 cells and can potentially stimulate cell proliferation through all three receptors.

Abstract

Large variations in nutritional intake have profound effects on the GH-insulin-like growth factor-I (IGF-I) axis in children and adults, but the effect of normal variations in nutrition on IGF-I concentrations is largely unstudied, particularly during puberty. We measured serum IGF-I concentrations in 325 sixth and seventh grade girls (12.4 +/- 0.7 yr) at the beginning of a multisite school-based health curriculum. The mean serum IGF-I level among the 243 girls with complete data was 573 +/- 244 micrograms/L. Pubertal stage was significantly associated with IGF-I (P less than 0.0001, by analysis of variance). Mean concentrations rose from 427 +/- 198 micrograms/L among those at the earliest pubertal stages to 639 +/- 219 micrograms/L among the mature girls. After adjusting for the association with the stage of pubertal development, serum IGF-I was not significantly associated with measures of body composition (body mass index, triceps skin fold thickness, waist/hip ratio, height, and weight). Additionally, IGF-I concentrations were not associated with nutritional intake (total calories, total protein, total fat, and total carbohydrate) or such measures of nutrition as serum iron, hemoglobin, red cell mean corpuscular volume, white cell count, and cholesterol. IGF-I concentrations, however, were significantly correlated with transferrin concentrations, another possible index of nutritional status (r = 0.29; P less than 0.0001). IGF-I is not a clinically useful index of nutritional status among normal pubertal girls.

Abstract

The effects of growth hormone therapy on the biochemical measures of bone metabolism were studied in 11 children aged 3.5 to 17 years who had familial hypophosphatemic rickets; five were male. Subjects were maintained on a regimen of stable doses of conventional therapy (calcitriol and phosphate). Subjects were studied at baseline receiving conventional therapy and during three sequential treatment periods: no therapy (4 weeks), growth hormone only (0.05 mg/kg per day for 4 weeks), and conventional therapy plus growth hormone (2 weeks). The nine youngest subjects were continued on a regimen of triple therapy for an additional 24 weeks. Serum phosphate averaged 0.93 +/- 0.13 mmol/L (mean +/- SD) at entry and decreased when the subjects were not receiving any therapy. During the 4 weeks of growth hormone only treatment, phosphate rose in all 11 subjects (0.70 +/- 0.08 mmol/L to 0.83 +/- 0.08 mmol/L). With triple therapy, phosphate remained higher than with no therapy. Calcitriol, osteocalcin, and parathyroid hormone increased as the subjects received growth hormone alone. Insulinlike growth factor I z scores rose significantly in response to growth hormone therapy alone. All nine subjects receiving 6 months of triple therapy increased their growth rate z scores. Exogenous growth hormone therapy may be useful in familial hypophosphatemic rickets.

Abstract

Insulin-like growth factor (IGF)-I and -II are known to play a major role in fetal and early postnatal growth. The IGF binding proteins (IGFBPs) are thought to be important in modulating the actions of the IGFs. In this paper, the effect of malnutrition in the neonatal rat on serum IGFs and IGFBPs and hepatic IGFBP messenger (m) RNA was examined. Control (C) dams (n = 9) were allowed ad libitum intake, whereas restricted (R) dams (n = 9) were limited to 50% of ad libitum intake throughout lactation, which results in decreased milk production and malnutrition of pups suckling on restricted dams. A subset of pups were cross-fostered from the R-dams to the C-dams from days 15-19 postpartum (PP) to investigate the effect of nutritional repletion (refed). Pups were killed on days 8, 12, 15, and 19 PP and liver and blood collected. Serum IGF-I and -II concentrations were measured by RIA after acid-chromatography to remove IGFBPs. Serum IGFBPs were characterized by Western ligand blot. Hepatic mRNA for IGFBP-1, -2, and -3 were determined by northern analysis. Body weight (BW) of R-pups was significantly less than C-pups by day 10 PP (P less than or equal to 0.05), and mean BW at day 19 was 56% of the C-pups. Refeeding from days 15-19 resulted in a significantly greater rate of growth vs. R-pups (3.2 vs. 0.9 g/day), and mean BW of refed pups at day 19 PP was 75% of C-pups. Malnutrition caused a significant reduction in both serum IGF-I and -II after day 12 PP, while causing an elevation in serum IGFBP-2. IGFBP-1 and IGFBP-2 mRNA expression were not significantly affected at days 8 and 12, but were elevated in livers of day 15 and 19 pups. Malnutrition caused a delay in the development shift from IGFBP-2 to IGFBP-3, which normally occurs between day 15 and 19 in the rat. Refeeding raised serum IGF-I and -II levels to those found in the C-pups and a trend toward normalization of IGFBP profiles. In conclusion, IGFs and IGFBPs are differentially regulated during neonatal malnutrition. The decrease in IGF peptide and induction of IGFBP-1 and -2 may provide protective mechanisms by inhibiting growth during malnutrition.

Abstract

Variation in the waist/hip ratio (WHR) may be related to changes in hormonal secretion associated with pubertal maturation. We therefore studied the effects of race, pubertal development, and body fatness on WHR during adolescence in a multiethnic population. A total of 688 white, Asian, and Hispanic female adolescents (mean (+/- SD) 12.4 +/- 0.7 years), participating in the evaluation of a multisite school-based health education program, were included in these analyses. Self-assessed stage of puberty and measurements of height, weight, waist circumference, and hip circumference were obtained from each participant. The WHR and age-adjusted body mass index were calculated. Analysis of covariance demonstrated that puberty significantly affects hip circumference and WHR but not waist circumference among female adolescents. Age and fatness, as reflected by age-adjusted body mass index, contributed significantly to both circumferences and to the WHR. There was a significant effect of ethnicity on hip circumference but not on waist circumference or the WHR. These results confirm that pubertal stage exerts a significant effect on the hip circumference and WHR in female adolescents, even after the effects of fatness and age are controlled. Studies of body fat distribution during late childhood and adolescence should include assessments of pubertal maturation.

Abstract

Weight-for-height indexes are often used in the clinical assessment of obesity in children and adolescents. The direct measurement of adiposity, using hydrostatic weighing and other techniques, is not feasible in studies involving young children or with large numbers of older subjects. Ratios of weight relative to height, such as the body-mass index (weight/height), may be used as indirect measures of obesity and correlate with more direct measures of adiposity. Using data from the First National Health and Nutrition Examination Study, 1971 to 1974, standardized percentile curves of body-mass index for white children and adolescents were developed. These curves may be used to monitor the body-mass index of white children and adolescents longitudinally and for comparing an individual with others of the same sex and age.

Abstract

IGF-I and -II are peptide growth factors that may be important contributors to the growth-promoting properties associated with milk. IGF in extracellular fluids, including serum and milk, are carried by specific high-affinity binding proteins (IGFBP). In this study, the levels of IGF-I and -II in rat serum and milk were quantified by specific RIA, and the IGFBP were characterized using Western ligand blotting and autoradiography throughout lactation. The levels of IGF-I in both milk and maternal serum decreased during lactation. Serum IGF-I decreased from 743 +/- 187 micrograms/L on d 1 to 391 +/- 106 (mean +/- SD) on d 21 of lactation, and milk IGF-I levels fell from 30 +/- 10 to 13 +/- 8 micrograms/L. Levels of IGF-II in serum and milk were much lower than IGF-I, and were unaffected by lactation. In maternal serum, several IGFBP were identified: IGFBP-3, which migrates as four glycosylated bands with apparent Mr from 38 to 42 kD and one to two nonglycosylated bands with apparent Mr of 28 to 29 kD, and an IGFBP with an apparent Mr of 24 kD. In milk, IGFBP-3, the 24-kD binding protein, and a third IGFBP with an apparent Mr of 29 kD were identified. Treatment of milk and serum with Endoglycosidase F reduced the four glycosylated IGFBP-3 bands (38-42 kD) to two bands with apparent Mr of 35 and 32 kD. In rat milk, but not adult rat serum, the IGFBP with an apparent Mr of 29 kD was immunoprecipitable by an antibody that recognizes IGFBP-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Normal adult human keratinocytes in monolayer culture and SCL-1, a skin-derived squamous-cell carcinoma cell line, were investigated for the expression of receptors for insulin-like growth factors (IGF) and insulin. As demonstrated by affinity crosslinking, radiolabeled IGF-1, IGF-2, and insulin bound specifically to both cell types. Each cell expressed type I IGF receptors, with affinity for IGF-1 greater than IGF-2 much greater than insulin. Insulin receptors, with highest affinity for insulin, were also present on both cells. However, keratinocytes and SCL-1 cells differed in 125I-IGF-2 binding. 125I-IGF-2-bound to both type I and type II IGF receptors in normal keratinocytes, but bound predominantly to membrane-associated IGF binding proteins in SCL-1. IGF-1 was slightly more potent than IGF-2 in stimulating growth of both keratinocytes and SCL-1 cells. In keratinocytes, concentrations of IGF-1 ranging from 5-100 ng/ml, and of IGF-2 from 50-100 ng/ml, resulted in a significant increase in cell number. At the maximum dose of 100 ng/ml, either IGF-1 or IGF-2 caused a 2.3-times increase in cell number. In SCL-1 cells, IGF-1 was more potent than IGF-2 or insulin at lower concentrations, but either IGF-1 or IGF-2 at the maximal concentration of 333 ng/ml stimulated a 4.7-times increase in thymidine incorporation. The stimulatory effect of insulin in SCL-1 was 10-50 times less potent than that of the IGF. The effect of either IGF on SCL-1 was completely inhibited by the type I IGF receptor antibody alpha IR-3, suggesting that both IGFs are mitogenic through the type I IGF receptor. Insulin action was partially blocked by alpha IR-3, suggesting that insulin can act through both the insulin and type I IGF receptors. It thus appears that IGF-1 and IGF-2 are mitogens for normal and transformed human keratinocytes and that their actions are primarily mediated through the type I IGF receptor, whereas insulin is a mitogen through both the IGF-1 receptor and the insulin receptor.

Abstract

Renin, secreted into the blood by the juxtaglomerular cells of the kidneys, is derived from a larger precursor, prorenin. Plasma prorenin activity is increased in patients with insulin-dependent (Type I) diabetes mellitus who have microvascular complications of their disease. We undertook this study to determine prospectively whether rising prorenin activity can predict the development of complications in young patients with Type I diabetes.Plasma prorenin was measured in 135 children and adolescents with Type I diabetes. The mean (+/- SE) plasma prorenin activity among the 32 patients over the age of 10 years who had had uncomplicated diabetes for 0.1 to 5 years was 8.43 +/- 0.58 ng of angiotensin I per liter.second, as compared with 7.06 +/- 0.32 in 37 control subjects of the same age (P less than 0.05). In the 9 patients older than 10 who had retinopathy or overt albuminuria, the mean plasma prorenin activity was 13.09 +/- 1.43 ng of angiotensin I per liter.second (P less than 0.0001). In 34 patients 10 years old or older with uncomplicated diabetes, 3 to 13 measurements of plasma prorenin activity were taken during a follow-up period of 6 to 39 months. Urinary albumin was determined at each visit, and the patients had regular retinal examinations. Only 1 of the 20 patients who had consistently normal plasma prorenin values had overt albuminuria (ratio of urinary albumin to creatinine, greater than 0.017) or retinopathy, whereas one or both of these complications appeared in 8 of the 14 who had at least one high prorenin value. The plasma prorenin value was significantly higher in these eight patients at least 18 months before a complication was found.Increased plasma prorenin activity identifies a group of young patients with diabetes who are at high risk for retinopathy or nephropathy.

Abstract

Growth hormone releasing hormone, a 44-amino acid peptide (GHRH-44), was administered (1 micrograms/kg i.v.) to 6 normal controls, 10 schizophrenic subjects, and 7 depressed subjects. A significantly lower growth hormone (GH) response was found in the schizophrenic and depressed groups. Two molecular forms of GH, 22K GH and 20K GH, were also measured but did not further differentiate the three groups of subjects.

Abstract

Human breast cancer cells (HBCC) secrete at least four different forms of IGFBPs. We have previously demonstrated that hIGFBP-1 is a minor component of IGFBPs secreted by Hs578T cells and is absent in CM from MCF-7 cells. In our present report, we describe the immunological and structural relationship of HBCC IGFBPs to hIGFBP-2 and hIGFBP-3. Analysis of conditioned media (CM) from Hs578T by Western ligand blotting revealed three IGFBPs of apparent Mr = 38K, 28K, and 24K; CM from MCF-7 revealed only two IGFBPs, of apparent Mr = 31K and 24K. Immunoprecipitation studies with polyclonal antibodies raised against hIGFBP-2 and hIGFBP-3 demonstrated that the 38K IGFBP in Hs578T CM is immunologically related to hIGFBP-3, while the 31K IGFBP in MCF-7 cells is related to the hIGFBP-2. Analysis by Northern blot demonstrated that MCF-7 cells contained mRNA for hIGFBP-2, while Hs578T cells contained the mRNA characteristic of the hIGFBP-3. The identity of the 24K IGFBP remains unknown, and may represent a distinct IGFBP. Of note, assay of CM following removal of BPs by acid chromatography demonstrated no detectable IGF-I or -II. The role of these IGFBPs in HBCC is of interest in view of the potential modulation of IGF actions by these proteins.

Abstract

Clinical testing of growth hormone (GH) sufficiency is a controversial area in endocrinology. Due to the episodic nature of endogenous GH secretion, diagnosis of GH deficiency has been defined as a failure to achieve normal GH levels in response to at least two stimuli. This testing is associated with significant patient morbidity and cost. We analyzed our experience over a 4-y period to determine whether clinical or biochemical variables could be used to predict the results of a specific GH testing procedure. Of 180 cases analyzed (67% male, mean age 8.89 +/- 4.39 y, range neonate-16 y), eight cases had incomplete GH testing results. Of the remaining 172, 19 were GH deficient (GH level less than 7 ng/mL). Younger age, higher body mass index and a greater degree of bone age delay were characteristic of the GH-deficient population; however, none of these variables alone was of diagnostic utility. Serum IGF-I level was below the normal range for 81% of the GH deficient and 47% of the GH-sufficient children; and was the only single variable that provided a reasonable between-group distinction. Discriminant analysis resulted in development of a new variable, based on IGF-I z scores, chronologic age, degree of bone age delay, and body mass index, which would have allowed exclusion of GH deficiency without provocative testing for 58% of the GH sufficient population, whereas permitting the diagnosis of GH deficiency for all GH-deficient subjects. Our data are dependent on the IGF-I assay method and the clinical definition for GH deficiency; therefore, the calculated predictive values are not applicable to all clinical populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

A high plasma prorenin is a marker of microvascular complications of diabetes. We have followed 56 adults and 120 children with uncomplicated insulin-dependent (type 1) diabetes. When plasma prorenin rises above the normal range in an adolescent or adult with type 1 diabetes, signs of nephropathy, retinopathy, or neuropathy follow within one to two years. The earliest sign may be intermittent microalbuminuria, which can often be abolished by improved control of hyperglycemia. The association between increased plasma prorenin and complications of noninsulin-dependent (type 2) diabetes is less reliable in patients with hypertension and in those receiving medication that affects plasma prorenin. The oral hypoglycemic agent, glipizide, lowers plasma prorenin, but its effect on prognosis is unknown. Plasma prorenin and renin decline as blood pressure rises, whereas the prevalence of micro- and macroalbuminuria increases. Many drugs used to control hypertension affect the level of prorenin. In the majority of our patients with type 2 diabetes who are hypertensive or are taking a medication that affects plasma prorenin, microalbuminuria may prove to be a more reliable warning of vascular complications.

Abstract

An unusual form of X chromosome aneuploidy, 47,XX,psu dic(X)(p11.2), was found during an evaluation for short stature of a prepubertal girl. Unlike 45,X, 47,XXX, 48,XXXX, and 49,XXXXX females, this patient is phenotypically normal except for her short stature, which appears to be unrelated to her chromosome abnormality. X chromosome inactivation studies disclosed inactivation (late replication) of one normal X and the abnormal X chromosome in all cells examined from this patient. Therefore, she is disomic for early-replicating distal Xp loci, found in inactivated X chromosomes, and thought to remain active after lyonization. These data suggest that the presence of three or more copies of the early-replicating, active Xp loci may be responsible for the cognitive deficits and other phenotypic abnormalities seen in and other phenotypic abnormalities seen in polysomy X females.

Abstract

The insulin-like growth factor binding proteins (IGF-BPs) are structurally and immunologically distinct from the IGF type 1 or type 2 receptors and are characterized by two major forms: a large, GH-dependent BP found in human plasma (Mr = 150 k) and a small GH-independent BP (Mr = 28-42 k) present in human plasma, amniotic fluid, and HEP G2 cells. Using affinity cross-linking techniques, we have identified several binding proteins secreted by human breast cancer cell lines (Hs578T, MDA-231, T-47D, and MCF-7). Under nonreducing conditions these proteins migrated at an apparent Mr = 35, 28, 27, and 24 k, while reducing conditions revealed bands of apparent Mr = 35, 32, 27, and 24 k. Competitive binding studies in T-47D-conditioned media demonstrated that these BPs bound more IGF-II than IGF-I, and that IGF-II potently inhibited binding of either IGF-I or -II. Immunological studies using a polyclonal antibody against the HEP G2 small BP revealed no immunoreactive BP in conditioned media from MCF-7 and T-47D and only slight immunoreactivity in conditioned media from Hs578T and MDA 231. Analysis by Northern blot, using a probe from the cDNA sequence of the HEP G2 BP, demonstrated that Hs578T and MDA-231 cell lines contained small amounts of the 1.65 kilobase mRNA characteristic of the HEP G2 BP, while MCF-7 and T-47D tested negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

As part of a blinded, randomized, placebo-controlled study of dexamethasone therapy in 27 preterm infants with bronchopulmonary dysplasia, we investigated the effect of 7 days of high-dose glucocorticoid therapy on the hypothalamic-pituitary-adrenal axis. Before therapy the median basal cortisol concentration in all infants was 8.2 micrograms/dl (226 nmol/L). After stimulation with 1-24 ACTH, the serum cortisol concentration rose in all infants to a median concentration of 23.5 micrograms/dl (649 nmol/L), resulting in a median rise of 13.4 micrograms/dl (37 nmol/L). Immediately after 7 days of glucocorticoid therapy basal and peak cortisol concentrations were significantly decreased in the dexamethasone group. The rise in serum cortisol following 1-24 ACTH, however, remained equivalent in both groups. Ten days after the end of therapy basal and peak cortisol concentrations in the dexamethasone group had returned to levels equivalent to those seen in the placebo group. Weight gain was markedly diminished while the infants were receiving dexamethasone. Weight gains were, however, equivalent 10 days after the end of treatment. These data indicate that 7 days of dexamethasone therapy has significant but short-term effects on cortisol secretion and possibly on weight gain.

Abstract

We studied 108 subjects (age range, 4 to 76 years) to determine the effect of age on prorenin (inactive renin), active renin, and plasma renin activity in normal children, adolescents, and adults. Children and adolescents had lower prorenin concentrations and higher plasma renin activity and active renin concentrations than did adults. Prorenin concentrations were positively correlated with age over the range of 4 to 76 years, while plasma renin activity and active renin concentration were negatively correlated with age. Plasma prorenin and active renin concentrations from umbilical cord blood samples obtained from 11 newborns and arterial samples obtained from five infants were higher than those in samples obtained from children or adults.

Abstract

The description of the cellular localization of insulin-like growth factor (IGF) receptors in the central nervous system (CNS) remains incomplete, as do the descriptions of changes in their characteristics with respect to different developmental stages. We, therefore, performed affinity labeling studies in microsomal membrane preparations of adult and fetal rat brain and liver tissues with [125I]IGF-I and [125I]IGF-II. These studies demonstrated tissue- and developmental stage-specific structural variants of type I receptor alpha-subunits as well as type II receptors. The adult rat brain type I alpha-subunit had an apparent mol wt (Mr) of 127,000, whereas those of adult and fetal rat liver measured 140,000. Fetal rat brain microsomes, however, had two types of type I receptor alpha-subunits measuring 130,000 and 120,000 Mr. The larger subunit from fetal brain consistently migrated at an apparent Mr of 3,000, greater than subunits from adult brain. Both type I and II receptors were more abundant in fetal liver and brain than in adult tissues. Affinity labeling was also performed directly to monolayers of cultured fetal brain neurons and newborn astrocytes. These studies detected both type I and II receptors on the surfaces of both types of cells. However, only the high Mr (140,000) form of the type I alpha-subunit was detected in cultured CNS cells, suggesting that expression of low Mr variant receptors is altered in vitro. Type II receptors were demonstrated by immunohistochemistry in adult rat hypothalamic neurons. However, the majority of neurons did not react with type II receptor antibody. This finding implies that only a minority of hypothalamic neurons are capable of responding to IGF-II via type II receptors. On the other hand, all astrocytes had striking type II receptor immunoreactivity. This signifies a more general biological role for this receptor in astrocytes compared with neurons. These results suggest that different tissue-, developmental stage-, and cell-specific processes are mediated by IGF receptors and suggests new directions in which to explore potential biological actions for these receptor-ligand systems in the CNS.

Abstract

The insulin like growth factors (IGFs), potent mitogens for a variety of normal and transformed cells, have been reported to be secreted by several human breast cancer cell lines (BC). We have investigated the binding characteristics of IGF-I and -II in four human BC: MCF-7, T-47D, MDA 231 and Hs578T. Binding studies in microsomal membrane preparations detected high specific binding for both IGF in all four BC studied. Cross-linking with 125I-IGF-I, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reduced conditions, revealed the presence of an alpha subunit of apparent Mr = 130,000 in MCF-7, T-47D and MDA 213 cells. When 125I-IGF-II was cross-linked, a major band of apparent Mr = 260,000 was seen in all BC. This band was inhibited by IGF-II, but not by insulin. Cross-linking of 125I-IGF-I to conditioned media from BC demonstrated the presence of three binding proteins of apparent Mr = 45,000, 36,000 and 29,000 in all BC but T-47D, in which the 36,000 band was not seen. These data demonstrate that BC possess classical receptors for both IGF-I and -II and, furthermore, that BC produce specific binding proteins for these growth factors.

Abstract

To evaluate the effects of growth-promoting therapy on carbohydrate metabolism in girls with Turner syndrome, we determined glucose and insulin concentrations during oral glucose tolerance tests (OGTTs) at baseline and after 5 days, 2 months, and 12 months of treatment with growth hormone (GH), oxandrolone, or a combination of GH and oxandrolone, or after the same intervals with no therapy. Before therapy, subjects had a significantly greater glucose response during OGTT than published normal control values. There were no significant changes in mean fasting glucose, cholesterol, or triglyceride concentrations in any of the treatment groups. The integrated glucose concentrations rose significantly over baseline values in the oxandrolone group at 2 and 12 months and in the combination group at 5 days. There were significant increases in the mean integrated insulin concentrations at 2 and 12 months for the group receiving oxandrolone alone and at all three times for the group receiving combination therapy. Thus oxandrolone, alone or in combination with GH, had significant effects on carbohydrate metabolism in subjects with Turner syndrome, whereas GH alone did not.

Abstract

We reviewed the effects of a brief course of testosterone enanthate (four intramuscular injections of 200 mg at three-week intervals) on pubertal advancement and final adult height in 50 male patients with delayed puberty. Although those treated with testosterone were slightly older than a group of 38 untreated subjects, the two groups had similar baseline mean bone age delays, height z scores, Tanner stages, predicted adult heights, growth rates, and midparental heights. Four months after baseline, the treated group had a significantly greater mean increase in the height z score and sexual maturation index. At 12 months, the mean increase in the sexual maturation index remained greater in the treated group. Among treated and untreated subjects older than 17 years, there was no significant difference in the absolute height z score. Over 95% of treated subjects were satisfied with the effects of therapy.

Abstract

Linear growth retardation and adult short stature are usual characteristics of Prader-Willi syndrome. Several lines of evidence suggest that a deficiency in growth hormone (GH) secretion may contribute to this abnormal growth pattern. We have recently reported observations in 4 children with Prader-Willi syndrome treated with GH. This report extends our observations in 2 of these cases. Both cases had abnormally low growth rate, normal stimulated GH levels, and low somatomedin-C levels prior to therapy. GH treatment led to significant increases in linear growth rate and somatomedin-C levels. An additive effect of oxandrolone therapy on linear growth rate was demonstrated in one case. Our results support the possibility of a neuro-secretory GH deficiency in Prader-Willi syndrome and suggest a need for further investigations.

Abstract

The treatment of growth failure in children with documented GH deficiency remains the only noncontroversial indication for GH therapy. There are increasing data suggesting that GH may be useful in treating some children with Turner's syndrome and with NVSS. Further studies, however, are necessary to evaluate the long-term efficacy and safety of GH therapy in these children. The treatment of non-GH deficient children whose heights are within two standard deviations of the mean height for age is clearly inappropriate and should be avoided, despite parental protests.

Abstract

Using data from the large number of adolescents studied in cycle III of the National Health Examination Survey, we utilized a sexual maturity index to develop a set of growth curves that reduce the distortion caused by commingling height data from adolescents maturing at different rates. We also created a set of correction tables to be used with these curves to permit the calculation of an adjusted height percentile that compensates for the effects of the differing rates of pubertal maturation. These adjusted height percentiles should remain more constant throughout puberty than height percentiles obtained from traditional growth curves; they may thus be used to estimate final adult height with only data obtained during routine physical examinations, by assuming that subjects maintain their adjusted height percentile through adolescence to adulthood. Height predictions made in this manner compare favorably with predictions made using two clinically tested algorithms.

Abstract

Restricted supplies of insulin-like growth factor II (IGF-II) have severely limited investigation of the in vivo actions of this hormone. To circumvent this problem, we have developed an in vivo rodent model in which rat (r) IGF-II-secreting cells (18, 54-SF) are transplanted into congenitally immunodeficient (nude) rats and mice. These cells proliferate and form discrete tumors that contain rIGF-II and abundant IGF-II receptors. The tumors also secrete rIGF-II into the circulation, resulting in plasma rIGF-II concentrations many-fold greater than those in control rodents (81 +/- 19 vs. less than 10 ng/ml, rats; 159 +/- 28 vs. 18 +/- 5 ng/ml, mice; P less than 0.05, both groups). There was no significant difference between the tumor-bearing and control rodents in either body weight or tail length. The tumor-bearing rodents did have significantly lower concentrations of IGF-I (296 +/- 23 vs. 527 +/- 67 ng/ml, rats; 300 +/- 26 vs. 482 +/- 70 ng/ml, mice; P less than 0.05, both groups), suggesting that the increased concentrations of rIGF-II may have inhibited IGF-I production or secretion. This animal model may be used to explore the biological effects of increased plasma IGF-II concentrations.

Abstract

A 42-yr-old man with congestive heart failure and diabetes mellitus was found to have acromegaly and a pheochromocytoma. Serum GH-releasing hormone (GHRH) levels were elevated (2.34 ng/dl; normal, less than 0.02 ng/dl), suggesting that the acromegaly was caused by ectopic secretion of GHRH. Postmortem examination revealed that the right adrenal gland contained a pheochromocytoma in which GHRH was demonstrated by immunohistochemical studies. Gel permeation chromatography combined with the use of two GHRH antisera showed that GHRH-(1-44)-NH2 was a predominant form of the hormone. When the RNA from the tumor was extracted and analyzed by Northern gel blotting, two mRNA species were identified, with transcripts corresponding to 1600 and 780 base pairs. The pituitary gland was enlarged, but no distinct adenoma was found. Diffuse and nodular hyperplasia of somatotrophs in some areas resembling adenoma was identified on histological examination. These findings indicate that GH excess accompanied by somatotroph hyperplasia and acromegaly were secondary to a pheochromocytoma which secreted not only catecholamines but also GHRH.

Abstract

Data from the National Health Examination Survey (cycles II and III) provided a representative sample of 13,887 US youths (6 to 17 years of age) with which to examine the relationship between height (normalized for age and sex) and measures of intellectual development (Wechsler Intelligence Scale for Children) and academic achievement (Wide Range Achievement Test). Additionally, 2,177 subjects were studied first in cycle II and 2 to 5 years later in cycle III, forming a well-selected longitudinal study group in which to examine any association between linear growth and change in IQ scores. Wechsler Intelligence Scale for Children and Wide Range Achievement Test scores were significantly correlated with height in both cycle II and cycle III. However, no significant association between change in relative height and change in IQ scores could be detected in the longitudinal group. These data suggest that therapies designed to increase height are unlikely to alter measures of intellectual development or academic achievement.

Abstract

Acromegaly is rarely caused by the ectopic secretion of growth hormone releasing factor (GRF) from peripheral neuroendocrine tumours. We evaluated the ability of a recently developed somatostatin analogue (SMS 201-995, Sandoz) to reduce hormone levels and pituitary size in a young woman with acromegaly and Zollinger-Ellison syndrome secondary to a metastatic pancreatic islet cell tumour secreting GRF and gastrin. Gastrin, GRF, and growth hormone (GH) levels declined dramatically following the initiation of therapy with the analogue by continuous iv infusion. Although intermittent sc therapy was not effective in suppressing hormone levels, continuous sc infusion of SMS 201-995 has provided good control of both GRF and GH levels for nine months. Moreover, treatment with SMS 201-995 was associated with a substantial reduction in pituitary enlargement and an improvement in her gastric symptoms. Continuous sc infusion of SMS 201-995 may be useful in treating enlarged pituitaries resistant to other modes of therapy.

Abstract

Plasma samples from 68 growth hormone (GH)-deficient children (provocative serum GH level less than 7 ng/ml), 44 normal short children, and 197 children with normal height were assayed by specific radioimmunoassays for the somatomedin peptides, insulin-like growth factors (IGF)-I and -II. Eighteen percent of the GH-deficient children had IGF-I levels within the normal range for age, whereas 32% of normal short children had low IGF-I levels. Low IGF-II levels were found in 52% of GH-deficient children, but also in 35% of normal short children. However, only 4% of GH-deficient children had normal plasma levels of both IGF-I and IGF-II. Furthermore, only 0.5% of normal children and 11% of normal short children had low plasma levels of both IGF-I and IGF-II. We conclude that plasma levels of either IGF-I or IGF-II overlap in GH-deficient and normal short children, but that the combination of radioimmunoassays may permit better discrimination among normal, normal short, and GH-deficient children.

Abstract

The case of a 6-year-old boy with Peutz-Jeghers syndrome (PJS), gynecomastia, and multifocal and bilateral testicular tumors is described. Females with PJS are known to be at increased risk for developing gonadal tumors. This case and other reports from the literature suggest that males, as well as females, with PJS are at risk for developing gonadal tumors.

Abstract

The authors report a 15-year-old short, nonvirilized, prepubertal female whose peripheral karyotype revealed a mosaicism in which 62 percent of the cells had a karyotype of 45X, and the other 38 percent had a karyotype of 46X plus a small unidentified marker chromosome. Since the authors were unable to determine from the karyotype whether this marker was derived from an X or a Y chromosome and because of the high risk for neoplasia in abnormal gonads containing Y material, she underwent surgical exploration, with removal of gonadal tissue. Microscopic examination of the streak gonads revealed a mixture of dysgenetic ovarian and testicular type tissues. The presence of testicular-like tubules strongly implied the presence of Y material in the genotype. Review of the literature reveals at least 19 similar cases in which presumed sex chromosomal markers or fragments were found in phenotypically normal females. Because of the risk of gonadal neoplasia in patients with occult Y chromosomal material, gonadectomy is indicated when the origin of the marker chromosome is uncertain.

Abstract

We have previously shown that serum from young women receiving the same combined mestranol-norethindrone containing oral contraceptive (OC) preparation accelerated the proliferation of arterial smooth muscle cells (SMC) in tissue culture, and this in vitro effect was not a direct action of either of its estrogenic or progestogenic constituents. To identify the substance(s) which might contribute to this potentially atherogenic action, blood was obtained from 20 OC users and control women for the measurement of growth hormone, insulin, somatomedins (insulin-like growth factor IGF-I and IGF-II), and the platelet alpha-granule constituents platelet-derived growth factor (PDGF), beta-thromboglobulin, and platelet factor 4 (PF4). No difference was demonstrable between OC users and controls in the levels of any of these growth-promoting hormones, nor in plasma concentrations of any of the platelet alpha-granule proteins. These studies indicate that the enhanced mitogenicity found in OC sera is probably not attributable directly to these hormones or PDGF, and may instead result from an in vivo OC-induced alteration in other as yet unidentified mediators of cellular growth.

Abstract

GH secretion is stimulated by hypothalamic GH-releasing factor (GHRH) and inhibited by somatostatin. Since GH induces the production of insulin-like growth factors (IGF) in liver and other tissues, it is of interest to learn whether IGF alters GH release through long loop feedback inhibition. Pituitary adenomas which had been removed from six acromegalic patients were processed for dispersed cell cultures and/or cell membrane preparations. Binding studies using 125I-labeled IGF-I, IGF-II, and insulin revealed specific hormone binding for each ligand to cell membranes derived from four somatotropinomas. A partially purified somatomedin preparation inhibited basal and/or GHRH-stimulated GH release from cultured pituitary cells derived from three of four adenomas; there was no effect of somatomedin in one tumor. In a single tumor, insulin also partially inhibited GHRH-stimulated GH release. Additionally, in one nonadenomatous pituitary removed from a patient with diabetes mellitus, insulin and somatomedin inhibited GHRH-stimulated GH release, and insulin inhibited basal GH secretion. These results indicate that specific cell membrane receptors for somatomedin peptides and insulin may be found on cell membranes from GH-secreting tumors, and that somatomedins and insulin can inhibit GH release in cultured human somatotropinoma cells. Thus, these data suggest that somatomedins may exert feedback inhibition of GH secretion in some patients with acromegaly.

Abstract

Plasma renin exists in an active form or as an inactive zymogen that resembles a prorenin present in homogenates of human kidneys. We examined the relation of diabetes and its microvascular complications with the level of plasma inactive renin activated by dialysis to pH 3.3. Plasma inactive renin was measured in 235 diabetic patients and 90 nondiabetic controls. In the controls, the level of plasma inactive renin increased slightly with age but was never above 50 ng per milliliter per hour. In young diabetic patients studied within three years of the onset of diabetes the concentration of inactive renin was normal, and in some older diabetics without complications it remained within the age-adjusted normal range for many years. However, in patients with retinopathy or albuminuria, plasma inactive renin was above the normal range with few exceptions, reaching levels 50 to 200 per cent above the upper limits of normal in patients with nephropathy. The frequency of neuropathy was also significantly higher among patients with levels above the normal range. In 37 per cent of the diabetics followed during one to three years of conventional treatment, plasma inactive renin increased significantly, but in another group of diabetics under intensive treatment, the level rose in only 7 per cent and fell in 43 per cent. We conclude that there is a close association between a high level of plasma inactive renin and the presence of microvascular complications, and that the level of inactive renin can be modified by intensive treatment of diabetes.

Abstract

A 7-year-old girl had hyperaldosteronism due to an adrenal cortical adenoma, a rare, surgically remediable cause of hypertension. Although the plasma potassium concentration was only slightly below normal, and the plasma aldosterone concentration was in a high normal range, the consistently suppressed plasma renin activity suggested primary aldosteronism. This diagnosis was confirmed by the failure of saline infusion to lower the plasma aldosterone concentration. Glucocorticoid-remediable hyperaldosteronism was excluded when dexamethasone did not reduce the high plasma aldosterone concentration. An enlarged left adrenal gland was observed in the computed tomographic scan, and blood from the left adrenal vein contained much more aldosterone than blood from the right adrenal vein. Surgical excision of the left adrenal gland, containing an adenoma, was followed by a return of BP and biochemical measurements to their normal ranges. This case demonstrated the importance of a rational systematic approach in the evaluation of children with sustained unexplained hypertension and the need to obtain plasma renin activity values when either hypokalemia is present or initial investigations fall to provide a diagnosis.

Abstract

A young woman with acromegaly and Zollinger-Ellison syndrome associated with a GH-releasing factor (GRF)- and gastrin-secreting metastatic islet cell carcinoma was studied by means of specific antisera which recognize various regions of the GRF molecule. Using specific immunohistochemical techniques, the tumor cells were shown to contain GRF, gastrin, and gastrin-releasing peptide, but not GH. During a 4-h period, plasma GRF levels averaged 5.6 +/- 1.4 ng/ml (+/- SD), while GH levels averaged 148 +/- 71 ng/ml. GH secretion was pulsatile and increased after TRH administration. GRF RIAs may be useful in establishing the diagnosis of acromegaly secondary to the ectopic secretion of GRF.

Abstract

Ten unselected, apparently healthy short children who were capable of normal growth hormone secretion were given human growth hormone (0.1 U/kg 1M thrice weekly) for 6 months to determine whether such treatment might lead to an increase in growth velocity. During treatment, all patients increased their growth rate (from 4.3 +/- 0.3 cm/yr to 7.4 +/- 0.5 cm/yr P less than 0.001). No adverse effects were detected. During the four-day IGF generation test, IGF I and IGF II levels rose significantly from 0.32 +/- 0.04 U/ml to 0.62 +/- 0.13 U/ml and from 279 +/- 36 ng/ml to 434 +/- 49 ng/ml, respectively. However, the growth response was not predicted by either the acute rise in IGF I or that in IGF II. Human growth hormone in standard doses may be capable of inducing accelerated growth in some short children without growth hormone deficiency. Measurements of IGF I and II cannot be used to predict which children will respond.

Abstract

Primary cultures of rat anterior pituitary cells were assessed for the presence of specific receptors for insulin and for the somatomedin peptides, insulin-like growth factors I and II (IGF-I and IGF-II). Specific binding per 100,000 pituitary cells averaged 9.45 +/- 1.69% (mean +/- SD) for [125I]IGF-II, 0.83 +/- 0.06% for [125I]IGF-I, and only 0.11% for [125I]insulin, IGF-II was twice as potent as IGF-I in displacing [125I]IGF-II, while insulin was totally nonreactive, IGF-I was 5-fold more potent than IGF-II at displacing [125I]IGF-I and 1000-fold more potent than insulin. Scatchard analysis of [125I]IGF-II binding revealed a curvilinear plot, which could be resolved into a high affinity receptor with a Ka of 7.0 X 10(8) M-1 and 120,000 receptor sites/cell, and a low affinity receptor with a Ka of 1.1 X 10(8) M-1 and 720,000 receptor sites/cell. The existence of abundant high affinity somatomedin receptors (especially for IGF-II) on rat anterior pituitary cells is consistent with a potential role for these peptides in the regulation of GH secretion.

Abstract

The clinical and radiological findings in four children with septo-optic dysplasia are reported. All four had growth retardation associated with growth hormone deficiency, as well as varying degrees of ophthalmologic dysfunction. The CT scan findings spanned a spectrum from normal to the expected abnormalities involving the ventricular system and orbits. Only two of the four had an absent septum pellucidum. A third patient had normal CT scans except for optic nerve hypoplasia, while the fourth had entirely normal CT scans of both the brain and orbits. Because the anatomic defects of septo-optic dysplasia may be subtle, an apparently normal CT scan does not invalidate the clinical diagnosis of septo-optic dysplasia.

Abstract

To explore the effect of puberty on the somatomedins (SMs), a group of insulin-like peptides which mediate the action of GH on skeletal tissue, we measured SM-C/insulin-like growth factor-I (SM-C/IGF-I) and IGF-II by specific RIAs in 110 adolescents between the ages of 10 and 18 yr. All subjects were in good health and between the 5th and 95th percentiles for height. In both females and males, SM-C/IGF-I levels rose during puberty to a peak approximately 3-fold higher than the average adult level. The rise in SM-C/IGF-I levels corresponded better with the Tanner stage of the adolescents than with their chronological age. IGF-II levels did not rise during puberty and were slightly below adult levels. The dramatic rise in SM-C/IGF-I levels during puberty suggests a role for this SM peptide in the adolescent growth spurt. Furthermore, these data indicate that proper interpretation of SM-C/IGF-I levels during adolescence must include a knowledge of the patient's pubertal development.

Abstract

To explore the role of the somatomedins (SM) during human pregnancy, we have measured plasma levels of insulin-like growth factor I (IGF-I), IGF-II, and SM peptide content (SMPC) in 79 women in various stages of normal pregnancies. IGF-I and IGF-II were measured by specific RIAs, and SMPC was measured by a radioreceptor assay using human placental membranes. IGF-I and SMPC rose during pregnancy, showing a significant positive correlation with the length of gestation. Plasma levels of IGF-I in the third trimester averaged 324 ng/ml, a 33% increase over the first trimester average of 243 ng/ml (P less than 0.05). Although IGF-II did not correlate with the length of gestation, the third trimester average was significantly higher than the first trimester average (780 vs. 630 ng/ml; P less than 0.05). After delivery, both IGF-I and IGF-II levels rapidly dropped to levels significantly below those seen in the third trimester. The gestational rise in SMPC and plasma levels of both IGF-I and IGF-II supports the hypothesis that SM play a role in the regulation of fetal growth.

Abstract

The acute effects of synthetic methionyl human growth hormone produced by recombinant DNA technology were compared with those of pituitary human growth hormone in 22 healthy male volunteers. Both caused increases in somatomedin and triglycerides and decreases in blood urea nitrogen and cholesterol. By all indices measured, synthetic methionyl human growth hormone was equipotent with pituitary human growth hormone. The ability to make biologically active synthetic human growth hormone creates an essentially unlimited supply of growth hormone for the treatment of hypopituitarism and for the study of additional therapeutic indications.

Abstract

We have investigated the effects on carbohydrate metabolism of human GH produced by recombinant DNA technology (methionyl-hGH) compared with pituitary hGH. Twelve normal adult male subjects received four daily im injections of either methionyl-hGH or pituitary hGH in a double blind, crossover study. Oral glucose tolerance tests and assays of insulin binding to peripheral monocytes were performed before th initial administration and 12 h after the fourth injection of both hGH preparations. Both methionyl-hGH and pituitary hGH resulted in significant carbohydrate intolerance, with a rise in fasting plasma glucose from 96.6 +/- 2.9 to 105.9 +/- 3.0 mg/ml (mean +/- SEM) after pituitary hGH and from 96.2 +/- 1.5 to 107.5 +/- 3.3 mg/dl after methionyl-hGH (P less than 0.01). The area under the glucose tolerance curve increased by 34% after pituitary hGH and by 37% after methionyl-hGH. With both hGH preparations, carbohydrate intolerance was associated with marked hyperinsulinemia, with a rise in fasting plasma insulin levels from 9.4 +/- 1.2 to 33.2 +/- 7.8 microU/ml after pituitary hGH and from 7.4 +/- 1.1 to 45.8 +/- 11.1 microU/ml after methionyl-hGH (P less than 0.01). The integrated plasma insulin levels during the oral glucose tolerance test tripled after both hGH preparations. The pronounced insulin resistance could not be attributed to an alteration in insulin receptor concentrations. Both hGH preparations were associated with small reductions in insulin binding to monocytes at tracer concentrations, but the decline in binding was not statistically significant. The calculated binding sites per cell and Ke were not significantly altered by hGH administration. We conclude that methionyl-hGH and pituitary hGH are indistinguishable in their ability to induce insulin-resistant carbohydrate intolerance. This decrease in insulin sensitivity cannot be attributed to an alteration in insulin binding, and presumably represents a postreceptor defect in insulin action.

Abstract

Several reports have suggested that heart rate may be regulated by an ultradian biological rhythm with a period of about 90--100 min. Blood pressure and heart rate were collected from 10 Surgical Intensive Care patients at 5-min intervals and analyzed by computer. No 90-min rhthms were found, indicating this rhythm has no significant influence on heart rate or blood pressure in postsurgical patients.